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| United States Patent |
5,294,724
|
|
Jendralla
, et al.
|
March 15, 1994
|
4-hydroxytetrahydropyran-2-ones and the corresponding
dihydroxycarboxylic acid derivatives, salts and esters and a process
for their preparation
Abstract
4-Hydroxytetrahydropyran-2-ones and the corresponding dihydroxycarboxylic
acid derivatives, salts and esters, process for their preparation, their
use as pharmaceuticals, and pharmaceutical preparations and precursors.
Compounds of the formula I
##STR1##
and the corresponding open-chain dihydroxycarboxylic acids of the formula
II
##STR2##
in which X, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the
meanings indicated, and also their pharmacologically tolerable salts with
bases and their pharmacologically tolerable esters, processes for the
preparation of these compounds, their use as pharmaceuticals and
pharmaceutical preparations are described. In addition, compounds of the
formula III
##STR3##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X and Y have the
meanings indicated are described.
| Inventors:
|
Jendralla; Heiner (Frankfurt am Main, DE);
Wess; Gunther (Erlensee, DE);
Kesseler; Kurt (Bad Soden, DE);
Beck; Gerhard (Frankfurt am Main, DE)
|
| Assignee:
|
Hoechst Aktiengesellschaft (Frankfurt am Main, DE)
|
| Appl. No.:
|
578240 |
| Filed:
|
September 6, 1990 |
Foreign Application Priority Data
| Current U.S. Class: |
549/292; 560/17; 560/60; 560/61; 560/62 |
| Intern'l Class: |
C07D 309/30; C07C 069/612; C07C 321/04; C07C 321/26 |
| Field of Search: |
549/292
514/468
560/17,60,61,62
|
References Cited
| Foreign Patent Documents |
| 0216127 | Apr., 1987 | EP | 549/292.
|
| 0283217 | Sep., 1988 | EP.
| |
| 0341681 | Nov., 1989 | EP | 549/292.
|
| 0414206 | Feb., 1991 | EP.
| |
| 3632893 | Apr., 1988 | DE.
| |
| 3632893A1 | Apr., 1988 | DE.
| |
| 3722809 | Jan., 1989 | DE | 549/292.
|
| 3819999A1 | Dec., 1989 | DE.
| |
Other References
Carew, et al., "Antiatherogenic effect of probucol unrelated to its
hypocholesterolemic effect: Evidence that antioxidants in vivo can
selectively inhibit low density lipoprotecin degradation in
macrophage-rich fatty streaks and slow the progression of atheroscerosis
in the Watanabe heritable hyperlipidemic rabbit," Proc. Natl. Acad. Sci.
USA, vol. 84, pp. 7725-7729 (1987).
Nestel et al., "Effects of Probucol on Low Density Lipoprotein Removal and
High Density Lipoprotein Synthesis," Artheroscierosis, 38, pp. 203-209
(1981).
Eder, "A Symposium: New Developments in the Treatment of
Hypercholesterolemia--Probucol," The American Journal of Cardiology, vol.
57, No. 16, pp. 1H-54H (1986).
Fogelman, et al., "Malondialdehyde alteration of low density lipoproteins
leads to cholesteryl ester accumulation in human monocyte-macrophages,"
Proc. Natl. Acad. Sci., USA, vol. 77, No. 4, pp. 2214-2218 (1980).
Stokker, et al., "3-Hydroxy-3-methylglutaryl-coenzyme A Reductase
Inhibitors. 1. Structural Modification of 5-Substituted
3,5-Dihydroxypentanoic Acids and Their Lactone Derivatives," J. Med. Chem
1985, vol. 28, pp. 347-358 (1985).
|
Primary Examiner: Ivy; C. Warren
Assistant Examiner: Owens; A. A.
Attorney, Agent or Firm: Finnegan, Henderson, Farabow, Garrett & Dunner
Claims
We claim:
1. A 4-hydroxytetrahydropyran-2-one of formula I
##STR34##
or the corresponding open-chain dihydroxycarboxylic acid of formula II
##STR35##
wherein X is oxygen;
Y is oxygen or sulfur;
R.sup.1 is isopropyl or cyclopropyl;
R.sup.2 is hydrogen, isopropyl or p-fluorophenyl;
R.sup.3 is hydrogen, acetyl, isopropyl, p-fluorophenyl, or one of the
radicals
##STR36##
wherein M is hydrogen or sodium; R.sup.4 is hydrogen, isopropyl or
p-fluorophenyl; and
R.sup.5 is isopropyl or p-fluorophenyl;
and pharmaceutically acceptable salt or pharmaceutically acceptable ester
thereof.
2. A compound which has one of the following formulae:
##STR37##
and the corresponding dihydroxycarboxylic acid salts, pharmaceutically
acceptable salt or pharmaceutically acceptable ester thereof.
3. A process for the preparation of a compound as claimed in claim 1, which
comprises
a) reacting appropriately substituted phenols or thiophenols of the formula
III
##STR38##
in which X, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the
meanings indicated for formula I, with the optically pure mesylate of the
formula IV
##STR39##
to give the acetonide of the formula V
##STR40##
b) converting compounds of the formula V with removal of the protective
group into tert.-butyl .beta.,.delta.-dihydroxycarboxylates of the formula
II/1
##STR41##
in which X, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the
meanings indicated for formula I,
c) hydrolyzing the tert.-butyl esters of the formula II/i to give salts of
the formula II/2
##STR42##
in which X, Y, R.sup.1, R.sup.2, R.sub.3, R.sup.4 and R.sup.5 have the
meanings indicated for formula I and M is a pharmacologically tolerable
cation it also being possible to remove protective groups which may be
present,
d) cyclizing the tert.-butyl esters of the formula II/1 or, if appropriate,
the salts of the formula II/2 to the .beta.-hydroxylactones of the formula
I
##STR43##
e) if appropriate converting the hydroxylactones of the formula I into the
corresponding open-chain dihydroxycarboxylic acids of the formula II,
their salts or their esters, if desired converting the salts or esters
into the free dihydroxycarboxylic acids of the formula II or if desired
converting the dihydroxycarboxylic acids II into the salts or esters.
Description
The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA
reductase) plays a central role in the biosynthesis of cholesterol [A.
Endo, J. Med. Chem. 28, 401 (1985) ]. Inhibitors of this enzyme, in
particular mevinolin, synvinolin and eptastatin have been clinically
tested for the treatment of hypercholesterolemics. Structurally
simplified, fully synthetic analogs of these compounds have been described
[T.-J. Lee, TIPS 8, 442 (1987) ]. For some time, an involvement of lipid
peroxidation in the formation of arteriosclerotic lesions has also been
discussed. Thus, it has been observed that oxidatively modified forms of
low density lipoprotein (LDL) cause a great enrichment of cholesterol
esters in macrophages [M. A. Fogelman et al., Proc. Natl. Acad. Sci. USA
77, 2214 (1980)] and additionally lead to increased release of a number of
lysosomal enzymes and pathogenic mediators. Only recently, it was shown by
the use of probucol that the suppression of LDL oxidation is more
essential for the avoidance of atherosclerotic processes than its action
on the serum cholesterol level [D. Steinberg et al., Proc. Natl. Acad.
Sci. USA 84, 7725 (1987)].
In human medicine, probucol of the formula
##STR4##
is used for the treatment of hyperlipoproteinemia.
According to an incompletely researched mechanism, probucol lowers both LDL
and HDL. Probucol increases the rate of catabolism of LDL [P. J. Nestel,
T. Billington, Atherosclerosis 38, 203 (1981) ] and increases biliary
cholesterol excretion. Compared with a potent cholesterol biosynthesis
inhibitor (such as mevinolin), however, the plasma cholesterol-lowering
action of probucol is only poorly pronounced. Recently, the therapeutic
use of probucol has principally been traced back to the fact that probucol
in vivo prevents oxidative modification of LDL [Symposium: New
Developments in the Treatment of Hypercholesterolemia--Probucol, various
authors, Am. J. Cardiol. 57, 1H-54H (1986)].
The antioxidative and radical entrainer properties of probucol can be
traced back to the fact that probucol captures free radicals continuing a
radical chain-reaction ("chain propagating radicals") by giving off the
hydrogen atoms of its hydroxyl groups. Probucol is in this way transformed
into oxyl radicals which because of the resonance with the sulfur atoms in
the para-position are electronically stabilized and because of the
sterically-screening ortho-tert.-butyl substituents are unable to continue
the radical chain [W. A. Pryor et al., J. Am. Chem. Soc. 110, 2224
(1988)].
In summary, at the moment the following partial picture for the
pathogenesis of arteriosclerosis thus results:
Hypercholesterolemia is the result, inter alia, of a pathologically
retarded LDL clearing owing to defective LDL receptor regulation and (or)
structure. The prolonged half-life of the LDL particles in the plasma
increases the probability of their oxidative modification. Oxidized LDL
damage the endothelium owing to cytotoxic properties and are absorbed by
macrophages via a special scavenger receptor without feedback control, the
latter dying in the form of lipid-overloaded "foam cells", releasing
endothelium-damaging lysosomal enzymes and initiating other pathogenic
mechanisms [SMC proliferation (SMC=smooth muscle cell in the vascular
wall) etc.] Foam cell formation and SMC proliferation count
anatomically-pathologically as early processes of an arteriosclerosis
which has not yet been demonstrated clinically.
Consequently, it appears extremely desirable to find active compounds
which, after oral administration and good absorption, cause a marked
lowering of the plasma cholesterol level via potent inhibition of HMG-CoA
reductase and simultaneously have the probucol-typical antioxidative
radical entrainer properties. However, this combination of properties is
unknown among all hypolipidemic active compounds hitherto known [review:
D. R. Illingworth, Drugs 33, 259 (1987)].
Only those HMG-CoA reductase inhibitors which fulfill the necessary
condition that a suitably substituted aromatic compound is bonded via a
heteroatom X to the 4 (R) -hydroxy-6(S)
-methylene-3,4,5,6-tetrahydro-2H-pyran-2-one radical (formula A), which is
essential for HMG-CoA reductase inhibition, or its ring-opened
dihydroxycarboxylic acid form (formula B)
##STR5##
would have a chance of probucol-type properties. Compounds of the formulae
A and B, in which X is oxygen or sulfur, have been described in
a) European Patent Application A-0,216,127;
b) German Offenlegungsschrift 3,632,893 Derwent Abstract 88-99366/15);
c) German Offenlegungsschrift 3,819,999 (corresponding to EP-A-0,341,681,
corresponding to U.S. patent application Ser. No. 350,428);
d) C. E. Stoker et al., J. Med. Chem. 28, 347 (1985) page 350.
According to German Offenlegungsschrift 3,819,999, particularly potent
HMG-CoA reductase inhibitors are present if R.sup.1' in formula A or B
has the meaning isopropyl or cyclopropyl and R.sup.5' has the meaning of
a substituted phenyl, in particular p-fluorophenyl. Compounds of this type
were more active in vitro and in vivo than mevinolin.
Although these ortho-substituents come close to the two tert.-butyl
substituents of probucol with regard to their steric requirement, the
compounds of the application c) possessed no probucol-analogous
properties.
It has now surprisingly been found that on replacement of the p-substituent
R.sup.3' by the group Y-R.sup.3, where Y is a sulfur or oxygen atom and
R.sup.3 is a radical analogous to probucol
##STR6##
compounds of the formula I are obtained which are provided with the
antioxidative properties of probucol and also in some cases are very
potent HMG-CoA reductase inhibitors.
It has been found that compounds of the formulae I and II
##STR7##
and their pharmacologically tolerable salts with bases and their esters a)
inhibit the enzyme HMG-CoA reductase more strongly than mevinolin and to
about the same extent as compound C
(3(R),5(S)-dihydroxy-6[-2-(4-fluorophenyl)-4,6-diisopropylphenoxy]hexanoic
acid sodium salt, compare German Offenlegungsschrift 3,819,999, Example
8a),
b) reduce cholesterol biosynthesis or the cholesterol content more strongly
than mevinolin and compound C in cell culture, but in particular
considerably more strongly than would be supposed solely on the basis of
their inhibitory action on HMG-CoA reductase.
c) reduce the plasma cholesterol level more strongly than mevinolin in the
same dose after p.o. administration to rabbits (5 mg/kg/day), but in
particular reduce the plasma cholesterol level considerably more strongly
than would be supposed solely on the basis of their inhibitory action on
HMG-CoA reductase (cf. Table 4, and in this case also data for compound
C).
d) cause a lowering of VLDL and a strong lowering of LDL after p.o.
administration to Wistar rats (100 mg/kg/day), without HDL being lowered
(in contrast to clofibrate and probucol). The lowering of plasma
cholesterol in the rat test can unequivocally not be put down to HMG-CoA
reductase inhibition, since HMG-CoA reductase inhibitors cause no plasma
cholesterol lowering in the rat owing to rapid and strong
counterregulation of the enzyme synthesis ("enzyme induction") [see, for
example, Y. Tsujita et al., Biochim. Biophys. Acta 877, 50 (1986)].
e) inhibit the microsomal lipid peroxidation in vitro and are consequently
radical inhibitors/antioxidants. In cases in which compounds of the
formula I or II did not possess these properties (noticeably), they were
discovered in the underlying phenol building blocks of the formula III
##STR8##
The latter were discovered as the more substantial metabolites on
reaction of I or II with liver homogenate, i.e. they occur in vivo
possibly as a metabolite of the compounds of the formula I or II.
The present invention therefore relates to compounds of the formula I
##STR9##
in which X and Y are identical or different and are an oxygen atom or a
sulfur atom,
R.sup.1 and R.sup.5 are both isopropyl or are different and are an
isopropyl, cyclopropyl or phenyl radical, it being possible for the latter
to be monosubstituted to trisubstituted in the nucleus by fluorine,
chlorine, bromine, trifluoromethyl and/or alkyl or alkoxy each having 1 to
4 carbon atoms,
R.sup.2 and R.sup.4 are identical or different and are hydrogen or an
isopropyl, cyclopropyl or phenyl radical, it being possible for the latter
to be monosubstituted to trisubstituted in the nucleus by fluorine,
chlorine, bromine, trifluoromethyl and/or alkyl or alkoxy having 1 to 4
carbon atoms,
R.sup.3 is
a) hydrogen, methyl or ethyl
b) a straight-chain or branched alkyl radical having 3 to 8 carbon atoms,
which can be substituted by the radical of the formula
##STR10##
in which X, R.sup.1, R.sup.2, R.sup.4 and R.sup.5 have the abovementioned
meanings and Z is either a hydrogen atom, a pharmacologically tolerable
cation or the
4(R)-hydroxy-6-(S)-methylene-3,4,5,6-tetrahydro-2H-pyran-2-one radical of
the formula
##STR11##
or the corresponding 3(R),5(S)-dihydroxyhexanoic acid-6-yl radical of the
formula
##STR12##
its pharmacologically tolerable salts with bases or its pharmacologically
tolerable esters,
c) cycloalkyl having 3 to 8 carbon atoms or a phenyl radical which can be
monosubstituted to trisubstituted in the nucleus by halogen,
trifluoromethyl and/or alkyl or alkoxy each having 1 to 4 carbon atoms, or
d) acetyl with the condition that Y is oxygen,
and the corresponding open-chain dihydroxycarboxylic acids of the formula
II
##STR13##
their pharmacologically tolerable salts with bases and their
pharmacologically tolerable esters.
Preferred compounds are those in which the substituents R.sup.1 and R.sup.5
are not simultaneously phenyl and substituted phenyl or differently
substituted phenyl.
The radicals in the formulae I and Ii preferably have the following
meaning:
X: oxygen
Y: oxygen or sulfur
R.sup.1 : isopropyl or cyclopropyl
R.sup.2 : hydrogen, isopropyl or p-fluorophenyl
R.sup.3 : hydrogen, acetyl, isopropyl, 9-fluorophenyl,
##STR14##
R.sup.4 : hydrogen, isopropyl or p-fluorophenyl R.sup.5 : isopropyl or
p-fluorophenyl
The following compounds of the formula I are particularly preferred
##STR15##
and the corresponding open-chain dihydroxycarboxylic acids of the formula
II, their pharmacologically tolerable salts with bases and their
pharmacologically tolerable esters.
The invention further relates to a process for the preparation of the
compounds of the formula 1, and of the corresponding open-chain
dihydroxycarboxylic acids of the formula II, their pharmacologically
tolerable salts with bases and their pharmacologically tolerable esters.
The process comprises
a) reacting appropriately substituted phenols or thiophenols of the formula
III
##STR16##
X, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the meanings
indicated for formula I, with the optically pure mesylate of the formula
IV
##STR17##
to give the acetonide of the formula V
##STR18##
b) converting compounds of the formula V with removal of the protective
group into tert.-butyl .beta.,.delta.-dihydroxycarboxylates of the formula
II/I
##STR19##
which X, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the
meanings indicated for formula I,
c) hydrolyzing the tert.-butyl esters of the formula II/1 to give salts of
the formula II/2
##STR20##
in which X, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the
meanings indicated for formula I and M is the pharmacologically tolerable
cation of a base, preferably the sodium cation, it also being possible to
remove protective groups which may be present,
d) cyclizing the tert.-butyl esters of the formula II/1 or, if appropriate,
the salts of the formula II/2 to the .beta.-hydroxylactones of the formula
I
##STR21##
e) if appropriate converting the hydroxylactones of the formula I into the
corresponding open-chain dihydroxycarboxylic acids of the formula II,
their salts or their esters, if desired converting the salts or esters
into the free dihydroxycarboxylic acids of the formula II or if desired
converting the dihydroxycarboxylic acids II into the salts or esters.
As can be seen from the process described, the compounds of the formulae I
and II and their salts and esters are prepared in optically pure form with
the absolute configuration shown. In this absolute configuration, the
compounds form a particularly preferred subject of the invention. Since
malic acid, the starting material for the preparation of the mesylate of
the formula IV, is also commercially available in the inverted absolute
configuration [D(+)-malic acid] or as the racemate [DL-malic acid], the
antipodes of the compounds of the formulae I and II and their salts and
esters or the racemates of the compounds of the formulae I and II and
their salts and esters can also be prepared in the same manner.
Furthermore, more or less optically enriched compounds of both absolute
configurations can be obtained from the racemates of the compounds of the
formulae I and II and their salts and esters by the classical methods of
racemate cleavage. The invention thus also relates to the antipodes of the
compounds of the formulae I and II and their salts and esters, to the
racemates, and to optically enriched compounds.
Process step a)
The mesylate of the formula IV is obtained by mesylation of the optically
pure hydroxy compound of the formula VI
##STR22##
The preparation of the compound of the formula VI from commercially
available L(-)-malic acid is described in EP-A-0,319,847. The reaction of
the hydroxy compound VI to give the mesylate IV is carried out, for
example, by reaction with methanesulfonyl chloride in the presence of a
weak base. The methanesulfonyl chloride is advantageously employed in a
small excess (1.05-1.5 equivalents). The use of a methylene
chloride/pyridine mixture as the solvent is advantageous. Owing to the low
thermal stability of many mesylates, it is recommended to carry out the
reaction with cooling. The reaction temperature is advantageously kept
near 0.degree. C. by ice-cooling. With expedient working up (see Process
Example 26), the mesylate IV crystallizes spontaneously and can be
obtained in high yield and purity by filtering with suction and washing.
The coupling of III with IV is preferably carried out in the presence of a
base in aprotic polar solvents. The use of potassium carbonate as a base
and DMSO or HMPT as a solvent has proved particularly suitable. When using
sulfur-containing compounds III (i.e. X and/or Y=S), HMPT is expediently
used as the solvent. Occasionally, the use of a catalytic amount of
18-crown-6 accelerates the reaction and increases the yield of V. The
mesylate IV is expediently employed in a small excess (about 1.1
equivalents). The coupling can be carried out in a temperature range from
40.degree. to about 90.degree. C. The purity of the crude product
distinctly decreases with increasing reaction temperature. The optimum
temperature and the associated duration of the reaction depend on the
nature of the substituents, in particular the steric screening of the
nucleophilic group XH, in the compound of the formula III. A reaction
temperature of 60.degree.-70.degree. C. and a duration of reaction of
about 12-18 hours was advantageous for the preparation of the particularly
preferred compounds. Apart from the acetonide grouping, the two hydroxy
groups of the mesylate IV can of course also be provided with other
protective groups which are stable to the basic coupling conditions, for
example tert.-butyldiphenylsilyl groups.
Process step b)
In principle, any of the numerous methods which have been described in the
literature for the cleavage of ketals can be used for the preparation of
the compounds of the formula II/1. The use of 2-normal aqueous
hydrochloric acid as a catalyst in homogeneous organic solution
(THF/ethanol) at room temperature is preferred.
Process step c)
This step is a basic ester hydrolysis step. It can be carried out using a
large number of pharmacologically tolerable bases in aqueous,
aqueous-organic or, if metal hydroxides are used as bases, alternatively
in organic aprotic solvents. The use of a 1:1 (vol/vol) mixture of exactly
1.0 equivalent of an aqueous 1-normal sodium hydroxide solution and
ethanol at room temperature is preferred. Excesses of sodium hydroxide
solution should be avoided as sodium hydroxide and the sodium salt II/2
both have relatively good water solubility and can therefore only be
separated with difficulty. The course of the hydrolysis can be monitored
using silica gel TLC (chloroform/methanol 5:1). With most (but not with
all) esters of the formula II/1, extensive hydrolysis under the conditions
mentioned is also detected in that the initial suspension changes into a
clear homogeneous solution.
Process step d)
The direct conversion of tert.-butyl esters of the formula II/1 into the
hydroxylactones of the formula I is carried out using an excess of a
number of strong acids, preferably organic acids. In principle, any
organic solvent is suitable which has good dissolving power for the
tert.-butyl ester II/1 and is sufficiently inert to the strong acid. The
use of trifluoroacetic acid in methylene chloride solution at room
temperature is preferred. The reaction time is as a rule 1-5 hours. TLC
checking of the course of the reaction is recommended to avoid side
reactions. It is advantageous to neutralize the reaction mixture by
addition of sodium hydrogen carbonate with cooling and then to render it
neutral with sodium carbonate. Excess sodium carbonate is to be avoided as
the lactones I are very easily hydrolyzed to the salts II/2 even under
weakly basic conditions. The lactones I can be obtained in high yield and
purity by extraction.
The lactones I can be obtained from the salts II/2 by various procedures.
In each case, the salts II/2 are converted into the free
dihydroxycarboxylic acids of the formula II by careful acidification,
followed by ethyl acetate extraction. The latter can be cyclized to the
lactone I by treatment with 1-1.5 equivalents of a dehydrating reagent,
for example N,N'-dicyclohexylcarbodiimide or, preferably, a water-soluble
carbodiimide such as
N-cyclohexyl-N'-[2'-(N"-methylmorpholinium)ethyl]carbodiimide
para-toluenesulfonate (Cf. M. Fieser "Reagents for Organic Synthesis" 1,
181 and 11, 151) in an inert organic solvent, preferably methylene
chloride, at 10.degree.-35.degree. C., preferably at room temperature.
Better yields and product purities are as a rule obtained if, instead, the
carboxyl group of the free dihydroxycarboxylic acids of the formula II is
reacted to give an intermediate derivative which is activated with regard
to an intramolecular nucleophilic attack of the .delta.-hydroxy group. The
literature describes a large number of methods of this type for carboxyl
activation. The formation of acid halides, acid imidazolides, active
esters or mixed anhydrides is very widespread. The carboxylic acid of the
formula II is preferably reacted with 1.1 equivalents of triethylamine and
1.0 equivalent of ethyl chloroformate at 0.degree.-10.degree. C. in
absolute THF. The lactones of the formula I are formed in nearly
quantitative yield in reaction times of 1-2 hours.
Process step e)
These transformations are trivial and are to be carried out corresponding
to the instructions in the prior art, for example with bases in the case
of salt formation.
Substituted phenols or thiophenols of the formula III are required as
starting materials for carrying out process step a). Compounds of the
formula III in which X, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5
have the meanings indicated for formula I are new. They are therefore also
included in the subject of the present invention.
In German Offenlegungsschrift 3,819,999, a process for the arylation of
phenols is proposed which consists in first subjecting the phenols to an
electrophilic aromatic halogenation (halogen=bromine or iodine) and then
treating the monohalophenol under palladium(O) catalysis with an aryl
Grignard compound, a position-specific halogen-aryl replacement taking
place: the aryl radical only occurs in the position in which the halogen
atom was previously found. The compounds of the formula III were
synthesized using this reaction as a key step. The thiophenols can be
prepared from the phenols in accordance with the instructions in DE-A
3,632,893.
##STR23##
Starting materials for the synthesis of compounds of the formula III
according to scheme 1 are phenols or thiophenols of the formula VII or,
according to scheme 3, benzenes of the formula XIII. The compounds VII are
commercially available or known from the literature, if R.sup.2 or R.sup.4
do not have the meaning of a (substituted) phenyl radical. If R.sup.2 or
R.sup.4 in formula III is intended to have the meaning of a (substituted)
phenyl radical, the compounds VII can be obtained analogously to the
reaction described above, or the synthesis according to scheme 3 can be
used.
A regiospecific ortho-halogenation of phenols can be achieved using
N-haloamines in accordance with the instructions in the literature [E.
Schmitz, I. Pagenkopf, J. Prakt. Chem. 327, 998 (1985)]. Ranges of
application and process variants were described in detail by Schmitz and
Pagenkopf. Preferably, 1.1 equivalents of a commercially available 40%
strength aqueous dimethylamine solution are reacted at about -10.degree.
C. with the aqueous sodium hypobromide solution formed from 3.2
equivalents of sodium hydroxide and 1.02 equivalents of bromine to give
N-bromodimethylamine, which is extracted using carbon tetrachloride, then
dried. This solution is then added dropwise at -10.degree. C. to a
solution of 1 equivalent of the compound VII in carbon tetrachloride. The
ortho-brominated dimethylammonium salt precipitates, and is filtered off
with suction and converted into the free compound VIII by boiling with 2N
sulfuric acid. Since, according to scheme 1, phenyl or substituted phenyl
is introduced as the radical R.sup.5, compound VIII is reacted with the
phenyl Grignard reagent R.sup.5 -MgBr under palladium catalysis to give
compounds of the formula IX. The variants for carrying out the coupling
reaction and alternatives for palladium have been proposed in German
Patent Application 38 19 999.8. For the conversion of VIII and IX,
preferably 3 equivalents of the Grignard reagent formed from R.sup.5 -Br
and a small excess of magnesium turnings are prepared in THF and this
solution is then transferred at 60.degree. C. to a solution of 1
equivalent of the compound VIII and 3-5 mol-% of
tetrakis(triphenylphosphine)palladium(O) in THF. Complete reaction takes
place, depending on the nature of the substituents R.sup.1, R.sup.2,
R.sup.4 and R.sup.5, in the course of 1 hour-12 hours at 60.degree. C. The
introduction of the sulfur function into the para-position, compounds X
being formed, is carried out by thiocyanation. There are several
procedures for this step, which have been described in detail and compared
(for example J. L. Wood in Org. React. J, 240-266 (1946) and J. H. Clark
et al., J. Chem. Soc. Chem. Commun., 81 (1989)]. Preferably, 1 equivalent
of the compound of the formula IX and 5 equivalents of sodium thiocyanate
are suspended in methanol and a solution of 1.5 equivalents of bromine in
methanol is slowly added dropwise at about 15.degree. C. The reaction is
based on the formation and in situ reaction of dithiocyanogen (SCN).sub.
2.
If a solution of a thiocyanate of the formula X is added dropwise,
preferably at 25.degree.-50.degree. C., to preferably 6 equivalents of an
alkyl or aryl Grignard compound R.sup.3 -MgBr, preferably in THF as
solvent, thioethers of the formula III/I are obtained. If R.sup.3 is an
aliphatic radical, the thioether III/1 is also obtained if a solution of
the thiocyanate of the formula X and an excess of the sodium alkoxide
R.sup.3 ONa (preferably about 2 equivalents) is heated under reflux in the
alcohol R.sup.3 OH. The thioethers of the formula III/I correspond to the
formula III, with the limitation that Y must be sulfur. Numerous methods
are known to convert thiocyanates into the corresponding thiols. A review
is to be found, f or example, in K.-D. Gundermann and K. Humke in
"Methoden der Organischen Chemiell" [Methods of Organic Chemistry]
(Houben-Weyl), volume E 11; "Organische Schwefelverbindungen, Teil 1"
[Organic Sulfur Compounds, Part 1], Thieme Verlag (Stuttgart, 1985) page
59: "Thiole aus Thiocyansaureestern" [Thiols from Thiocyanic Acid
Esters]. Preferably, the reductive cleavage of the thiocyanates of the
formula X to give thiols of the formula III/2 is carried out using about
1.7 mole equivalents of lithium aluminum hydride in tetrahydrofuran under
reflux. The yields in this procedure are very high (>90%). In the presence
of atmospheric oxygen, the thiols of the formula III/2 undergo rapid
oxidative dimerization to the corresponding disulfides. They are therefore
expediently prepared by thorough degassing of the reaction solution under
an inert gas atmosphere. The thiols of the formula III/2 correspond to the
formula III, with the limitation that Y is sulfur and R.sup.3 is hydrogen.
There are several alternative methods for the introduction of the thiol
grouping into aromatic compounds of the formula IX. A review is to be
found, for example, in K.-D. Gundermann and J. Humke in "Methoden der
Organischen Chemie" [Methods of Organic Chemistry] (Houben-Weyl), volume E
11; "Organische Schwefelverbindungen, Teil 1" [Organic Sulfur Compounds,
Part 1], Thieme Verlag (Stuttgart 1985), pages 32-63: "Herstellung von
Thiolen" [Preparation of Thiols]. A synthetic route is described in detail
in scheme 1.
The reaction of the thiols of the formula III/2 to give the acetone
dithioketals of the formula III/3 is possible in principle using acetone
in the presence of an acidic catalyst analogously to the method described
for probucol. [M. B. Neuworth et al., J. Med. Chem. 13, 722 (1970)].
Compounds of the formula III/3 are obtained in 85-100% yield when the
thiols of the formula III/2 are heated to about 80.degree. C. in the
presence of catalytic amounts of p-toluenesulfonic acid in an inert
solvent, preferably benzene, containing 1.25-1.50 equivalents of
2,2-dimethoxypropane. The reaction time depends on the nature of the
substituents R.sup.1, R.sup.2, R.sup.4 and R.sup.5 and is as a rule 2-12
hours. The polar, mixed oxygen/sulfur ketal of the formula XI
##STR24##
occurs as an intermediate of the reaction and is the principal product
when the reaction is carried out at room temperature (1-2 hours). It is
slowly converted in the reaction mixture at room temperature, and rapidly
at about 80.degree. C., into the less polar product of the formula III/3.
The thioketals of the formula III/3 correspond to the formula III, with
the limitation that Y is sulfur and R.sup.3 is the radical
##STR25##
The process according to the invention is illustrated below by the reaction
of compound III/3 to give the final products of the formula I according to
scheme 2.
The reaction of the thioketals of the formula III/3 with the mesylate IV
according to process step a) leads to two different coupling products,
namely the monocoupling product V/1 and the dicoupling product XII. V/1
and XII can be separated by column chromatography without problems. They
are always both formed in the coupling, but their ratio can be influenced
by means of the reaction conditions. If, for example, only 1.2 moles of
the mesylate IV is used per mole of thioketal III/3, V/1 and XII are
formed approximately in the ratio 2:1 (about 70% total yield). On the
other hand, if 2.5 moles of the mesylate IV are employed per mole of
thioketal XII/3 and the reaction time is lengthened, the ratio V/1 to XII
is <1:3.
The separated products V/1 and XII can then be converted into the
mono(hydroxylactones) of the formula 1/1, the bis-(hydroxylactones) of the
formula I/2 (both formulae are special cases of the formula 1), their
open-chain dihydroxycarboxylic acids of the formula II, their salts or
their esters according to process steps b), c), d) and, if desired, e).
##STR26##
Substituted hydroquinones (phenols of the formula III in which X and Y are
oxygen) of the formulae III/4, III/5 and III/6, which are all special
cases of the building blocks with the formula III, can be prepared
according to the synthesis sequence indicated in scheme 3. The unusual
feature of this process is that the two hydroxy groups are only introduced
into the aromatic hydrocarbon of the formula XIX at the end of the
sequence. Furthermore, the two hydroxy groups of the compounds of the
formula III/4 can be differentiated by complementary processes in such a
way that either one or the other hydroxy group can specifically undergo
coupling with the mesylate IV. In monoacetates of the formula III/5, for
example, the "upper" hydroxy group of the hydroquinones III/4 was
protected; only the "lower" hydroxy group remains capable of coupling for
the reaction with compounds of the formula IV and thus obtains the meaning
of the XH group of the formula III where X=oxygen. The isopropyl group and
the substituent R.sup.7 the formula III/5 thus correspond to the
substituents R.sup.1 and R.sup.5 of the formulae I to III, while the
substituents R.sup.6 and R.sup.8 of III/5 correspond to R.sup.2 and
R.sup.4 of I to III.
In the monoacetate of the formula III/6, on the other hand, the "lower"
hydroxy group of the hydroquinones III/4 is protected. In III/6 the
"upper" hydroxy group consequently has the meaning of the XH group of the
formula III where X=oxygen. The isopropyl group and the substituent
R.sup.7 of the formula III/6 thus correspond to the substituents R.sup.2
and R.sup.4 of the formulae I to III, while the substituents R.sup.6 and
R.sup.8 of III/6 correspond to R.sup.1 and R.sup.5 of I to III.
It is known that, depending on the choice of the complementary
monoacetylation process, the substituent pairs R.sup.6 /R.sup.8 and
i-Pr/R.sup.7 can confer the meaning of ortho-substituents R.sup.1 /R.sup.5
or metasubstituents R.sup.2 /R.sup.4 in the final products of the formulae
I and II. The direct chemoselective esterification is always complementary
in compounds of the formula III/4 to the two-step process for
diacetylation, followed by chemoselective hydrolysis. The substituent pair
i-Pr/R.sup.7 has either a higher or a lower steric requirement than the
substituent pair R.sup.6 /R.sup.8.
Under mild conditions, the monoacetylation takes place distinctly more
rapidly on the less sterically hindered of-the two hydroxy groups of
III/4. On the other hand, if a diacetylation to give XXI is forced as a
result of more drastic reaction conditions and an excess of the
acetylating agent, the sterically less hindered hydroxy group is liberated
distinctly more rapidly than the hindered one in the subsequent
hydrolysis. The opposite product is preferably thus obtained compared to
the direct monoacetylation.
Starting materials for the synthesis of the hydroquinones III/4 or the
complementary protected hydroquinones of the formulae III/5 and III/6 are
the substituted benzenes of the formula XIII, which are known from the
literature and, for the most part, commercially available. Depending on
which of the two complementary acetylations is later carried out, R.sup.6
has the meaning which has been indicated for R.sup.1 or R.sup.5 in the
formula I and R.sup.7 has the meaning which has been indicated for R.sup.2
or R.sup.4 in the formula I--or vice versa.
Compounds of the formula XIV are obtained by Friedel-Crafts acetylation of
the benzenes XIII. The reaction is carried out using a small molar excess,
preferably about 1.05 equivalents, of acetyl chloride in the presence of
an excess of a Lewis acid, preferably about 1.2 equivalents of aluminum
chloride, in an inert dry solvent, preferably carbon disulfide. Optimum
reaction temperatures and times depend on the nature of the substituents
R.sup.6 and R.sup.7. As a rule, a temperature of close to -10.degree. C.
and a time of 1-about 6 hours is preferred. The acetylation takes place
almost exclusively in the ortho-position to the substituents R.sup.6 or
R.sup.7. If R.sup.6 and R.sup.7 are identical, only one product is formed.
If R.sup.6 and R.sup.7 are different, two products are formed, which have
to be separated. As a rule, purification or separation of the methyl
ketones XIV can be carried out by high vacuum distillation.
The alcohols of the formula XV are obtained in virtually quantitative yield
if an excess, preferably about 1.4 equivalents, of a commercial ethereal
methylmagnesium halide solution (for example a commercially available
ethereal methylmagnesium iodide solution) is added dropwise to an ethereal
solution of the methyl ketone XIV so that reflux is maintained. In
principle, these reactions can be worked up by extraction and the alcohols
XV purified by crystallization. However, it is advantageous to eliminate
water directly from the crude alcohols XV by heating them under reflux in
a water separator in the presence of a catalytic amount of a strong acid,
preferably para-toluenesulfonic acid, in a solvent which forms a
low-boiling azeotrope with water, but is only sparingly miscible with
this, preferably benzene or toluene.
The crude olefins of the formula XVI are converted into the compound of the
formula XVII by catalytic hydrogenation. A large number of catalysts are
described in the literature which are suitable for reactions of this type.
For reasons of safety and easier feasibility, the hydrogenation is
preferably carried out at room temperature under 1 atm of hydrogen. The
use of 1-2% by weight of 10% palladium on carbon and of n-hexane as
solvent has proven suitable for this purpose. As a rule, the compounds of
the formula XVII can be purified by vacuum distillation, but other
physical separation processes, such as recrystallization or
chromatography, are of course also possible.
Owing to a combination of electronic and steric factors, the electrophilic
aromatic bromination takes place under mild conditions with high
regioselectivity with the formation of compounds of the formula XVIII. In
order to avoid multiple bromination, an excess of bromine should be
avoided. Carbon tetrachloride has proven suitable as an inert solvent and
a spatula tip full of iron powder as a catalyst. The reaction is
preferably carried out at or below -10.degree. C. in order to achieve high
selectivity.
The replacement of the bromine atom of XVIII by a (substituted) aryl
radical R.sup.6 is best carried out by reacting XVIII with an equivalent
of magnesium turnings in THF under reflux to give the corresponding
Grignard compound. This Grignard solution is then transferred under inert
gas pressure in THF to a solution of about 1.05 equivalents of a
(substituted) aryl bromide or aryl iodide R.sup.8 -Hal and about 0. 01
equivalent of a palladium(O) catalyst, preferably
tetrakis(triphenylphosphine)palladium(O), and the reaction mixture is
heated under reflux. Frequently, the reaction can also be carried out by
preparing the Grignard compound R.sup.8 -MgHal and then adding this to a
solution of the aryl bromide XVIII and a catalytic amount of
Pd(PPh.sub.3).sub.4 in THF. Variants for carrying out the coupling
reaction and alternatives for palladium have been proposed (cf. German
Offenlegungsschrift 3,819,999). As a rule, the products of the formula XIX
can be purified by distillation in a pump vacuum.
The reaction of the hydrocarbons of the formula XIX to give the quinones of
the formula XX can be achieved using a number of oxidants. As a rule, the
yield of the reaction distinctly increases with increasing substitution of
the starting compound.
The addition of a large excess of a 5:1 (vol/vol) mixture of
trifluoroacetic acid and 70% strength aqueous hydrogen peroxide at about
-20.degree. C. to the hydrocarbon XIX is preferred. No heat of reaction or
reaction is observed at this temperature. If the cooling bath is then
removed and the mixture is stirred while warming to room temperature, a
sudden, extremely exothermic initiation of the reaction is observed in the
temperature range from about +10.degree. C. to +20.degree. C. Intensive
cooling of the reaction flask and the reflux condenser is then necessary
in order to keep the reaction under control. The pure, intensively yellow
quinones XX are obtained from the crude reaction product by column
chromatography or more simply by recrystallization. The quinones of the
formula XX can be reduced to the hydroquinones of the formula III/4 using
various reagents. H. Ulrich and R. Richter give a review in "Methoden der
Organischen Chemie" [Methods of Organic Chemistry] (Houben-Weyl), volume
VII/3a "Chinone Teil 1" [Quinones Part 1], Georg Thieme Verlag, Stuttgart
(1977), pages 648-653: "Umwandlung von p-Chinonen durch Reduktion"
[Transformation of p-quinones by reduction]. It is advantageous to add
about 5 mole equivalents of sodium borohydride to a solution of the
quinones XX in ethanol under inert gas. The course of the reaction is
detected by the decolorization of the originally yellow solution. The
ethanol is then removed in vacuo and the residue is decomposed with
intensive cooling using degassed hydrochloric acid. The aqueous phase is
immediately extracted using degassed diethyl ether and the ether is
removed in vacuo. The hydroquinones of the formula III/4 remain as
colorless powders which are washed with, for example, n-pentane and
filtered off with suction under inert gas. These hydroquinones undergo
very easy oxidation, especially in solution, being reconverted into the
yellow quinones XX. All solvents should therefore be oxygen-free in the
preparation of III/4. The hydroquinones III/4 are best reacted directly,
also under oxygen-free conditions, to give the monoacetates III/5 or
III/6, which are hardly sensitive to oxidation.
For the regioselective preparation of the monoacetates of the formulae
III/5 and (or) III/6, the hydroquinones of the formula III/4 are reacted,
for example at 0.degree. C., with 1.1-1.5 equivalents of acetic anhydride
in the presence of a base, preferably in anhydrous pyridine as a solvent.
The reaction time is 1-3 days depending on the nature of the substituents
R.sup.6, R.sup.7 and R.sup.8. In addition to a little starting material
III/4 and diacetate XX, the two monoacetates III/5 and III/6 are obtained
with a selectivity which is 4:1 to about 20:1, depending on the nature of
the substituents R.sup.6, R.sup.7 and R.sup.8.
The two monoacetates can be separated from one anothers, and from the
quinone XX and the diacetate XXI#by column chromatography on silica gel.
In the eluent cyclohexane/ethyl acetate 9:1. the sterically more greatly
hindered (formed to a smaller extent) monoacetate has a somewhat larger
R.sub.f value than the sterically less hindered (formed to a greater
extent) monoacetate (principal product). The diacetate XXI is distinctly
more polar. Mono- and diacetates of the formulae III/5, III/6 and XXI are
solids which, if required, can be further purified by recrystallization.
For the specific preparation of the diacetates of the formula XXI, the
hydroquinones of the formula III/4 are reacted with an excess, preferably
3-4 equivalents of acetic anhydride, in the presence of a base, preferably
in anhydrous pyridine as the solvent. The reaction temperature is about
0.degree.-40.degree. C. depending on the nature of the substituents
R.sup.6, R.sup.7 and R.sup.8 and the reaction time is about 1 hour to
several days.
Both in the mono- and the diacetylation, other acylating agents, for
example acetyl chloride, mixed anhydrides of acetic acid, acetic acid
imidazolide etc. can also be employed instead of acetic anhydride.
Occasionally, the yields in the mono- or diacetylation are distinctly
increased if 4-dimethylaminopyridine (DMAP, preferably 5-10 mol-%) is
employed as a catalyst, triethylamine is employed as a base and acetic
anhydride is employed as an acylating agent [G. Hofle, W. Steglich, H.
Vorbruggen, Angew. Chem. Int. Ed. 17, 569 (1978)]. All mild methods of
ester cleavage are in principle utilizable for the chemoselective
(regioselective) hydrolysis of the diacetates of the formula XXI. These
methods are prior art. It is crucial that only a little more than 1
equivalent of the base is employed (in order largely to avoid the
hydrolysis of both acetyl groups) and that the reaction temperature is
kept so low that the hydrolysis requires several days (maximum
selectivity).
The use of 1.1 equivalents of lithium hydroxide in
1,2-dimethoxyethane/water 3:1 (vol/vol) is expedient. Optimum reaction
temperatures and times depend on the nature of the substituents R.sup.6,
R.sup.7 and R.sup.8. As a rule, hydrolysis at room temperature, which
usually requires 1-5 days, leads to selectivities of 2-5 to 1.
High cholesterol levels, and the oxidative modification of the LDL and the
formation of "foam cells" with consequent pathogenic processes resulting
from this has been associated with a number of disorders which are
considered as consequences of arteriosclerosis, for example coronary heart
disease and cardiac infarct. The lowering of raised cholesterol levels and
the avoidance of LDL oxidation is therefore a therapeutic aim for the
prevention and treatment of such disorders. A starting point is the
inhibition or reduction of endogenous cholesterol synthesis. Inhibitors of
HKG-CoA reductase block cholesterol biosynthesis at an early stage. They
are therefore suitable for the prevention and treatment of disorders which
are caused by an increased cholesterol level. A reduction or lowering of
the endogenous synthesis leads to an increased absorption of cholesterol
from the plasma into the cells. An additional effect can be achieved by
simultaneous administration of bile acid-binding substances such as anion
exchangers. The increased bile acid excretion leads to increased
resynthesis and thus to increased cholesterol degradation (M. S. Brown, P.
T. Kovanen and J. L. Goldstein, Science 212, 628 (1981); M. S. Brown and
J. L. Goldstein, Spektrum der Wissenschaft 1985, 96 ). The compounds
according to the invention are inhibitors of HMG-CoA reductase. They are
therefore suitable for the inhibition or reduction of cholesterol
biosynthesis and thus for the prevention or treatment of disorders which
are caused by raised cholesterol levels in the blood, in particular
coronary heart disease, atherosclerosis and similar disorders. There are
indications (cf. Tab. 1-4) that the compounds according to the invention
moreover have a plasma cholesterol-lowering action according to another
kind of mechanism, which increases the plasma cholesterol reduction
achieved by the mechanism of HKG-CoA reductase inhibition. The compounds
according to the invention and (or) their building blocks of the formula
III moreover have an antioxidative, radical-inhibitory action. The
building blocks of the formula III are moreover metabolites of the
compounds according to the invention.
The invention therefore also relates to pharmaceutical preparations based
on compounds of the formula I or the corresponding dihydroxycarboxylic
acids of the formula II, their salts and esters, and the use of these
compounds as pharmaceuticals, in particular for the treatment of
hypercholesterolemia.
The compounds of the formula I or II and the corresponding salts or esters
are administered in various dosage forms, preferably orally in the form of
tablets, capsules or liquids. Depending on the body weight and
constitution of the patient, the daily dose varies in the range from 1 mg
to 2,500 mg, but preferably in the dose range 10 to 100 mg.
The compounds according to the invention can be used as lactones of the
formula I, in the form of the free acids of the formula II or in the form
of pharmaceutically acceptable salts or esters, in particular dissolved or
suspended in pharmacologically acceptable organic solvents such as mono-
or polyhydric alcohols such as, for example, ethanol or glycerol, in
triacetin, oils such as, for example, sunflower oil or cod liver oil,
ethers such as, for example, diethylene glycol dimethyl ether or,
alternatively, polyethers such as, for example, polyethylene glycol or,
alternatively, in the presence of other pharmacologically acceptable
polymer excipients such as, for example, polyvinylpyrrolidone or other
pharmaceutically acceptable additives such as starch, cyclodextrin or
polysaccharides. In addition, the compounds according to the invention can
be combined with additives which bind bile acids, in particular non-toxic,
basic anion exchanger resins which bind bile acids in a form which cannot
be absorbed in the gastrointestinal tract. The salts of the
dihydroxycarboxylic acids can also be administered as an aqueous solution.
The inhibition of cholesterol biosynthesis or the plasma cholesterol
reduction by the compounds of the formulae I and II according to the
invention were determined in various in vitro and in vivo test systems.
1) Inhibition of HKG-CoA reductase activity in solubilized enzyme
preparations from rat liver microsomes
HMG-CoA reductase activity was measured on solubilized enzyme preparations
from liver microsomes of rats which had been induced by conversion into
the day/night rhythm using cholestyramine (.RTM.Cuemid). (S,R).sup.14
C-HMG-CoA was used as a substrate, and the concentration of NADPH was
maintained during the incubation by a regenerating system. The separation
of .sup.14 C-mevalonate from substrate and other products (for example
.sup.14 C-HMG) was carried out by column elution, the elution profile of
each individual sample being determined. The regular addition of .sup.3
H-mevalonate was avoided as the determination gives the data relative to
the inhibitory action. The enzyme-free control, the enzyme-containing
normal mixture (=100%) and those containing preparation additives were in
each case treated together in one series of experiments. The sodium salts
of the dihydroxycarboxylic acids of the formula II were always employed as
the preparation in this test. Each individual value was formed as the mean
value of 3 parallel samples. The significance of the mean value
differences between preparation-free and preparation-containing samples
was evaluated by the t-test. The following inhibitory values, for example,
were determined for the HMG-CoA reductase from the sodium salts of the
compounds of the formula II according to the invention by the method
described above (IC.sub.50 (mol/l); molar concentration of the compound
per liter which is necessary for a 50% inhibition).
TABLE 1
______________________________________
IC.sub.50 (mol/l)
______________________________________
Standard mevinolin sodium salt
8 .times. 10.sup.-9
Compound C (German 2.3 .times. 10.sup.-9
Offenlegungsschrift
3,819,999, Example 8a)
Example
1 6 .times. 10.sup.-9
2 2 .times. 10.sup.-9
3 4 .times. 10.sup.-9
4 8 .times. 10.sup.-9
5 8 .times. 10.sup.-9
6 3 .times. 10.sup.-9
7 1 .times. 10.sup.-9
8 2 .times. 10.sup.-9
9 4 .times. 10.sup.-9
______________________________________
2) Inhibition of cholesterol biosynthesis in cell cultures (EEP G2 cells)
Determination of the inhibition of the incorporation of .sup.14 C-sodium
acetate in cholesterol
Monolayers of HEP G2 cells in lipoprotein-free medium were preincubated
with various concentrations of the sodium salts of the dihydroxycarboxylic
acids of the formula II for 1 hour. After adding .sup.14 C-labeled sodium
acetate, the incubation was continued for 3 hours. Tritium-labeled
cholesterol was added as an internal standard and an aliquot of the cells
was subjected to alkaline hydrolysis. The lipids were extracted using
chloroform/methanol 2: 1. After adding carrier cholesterol, the lipid
mixture was preparatively separated on TLC plates using chloroform/acetone
9: 1. The cholesterol zone was made visible by staining with iodine vapor,
additionally detected using a TLC radio scanner and then scraped off. The
amount of .sup.14 C-cholesterol formed was determined scintigraphically
and related to mg of cell protein. The same procedure was carried out with
cells from the Bame culture without preincubation with a test compound
(so-called "solvent control"). The potency of the test compounds was
determined by comparison of the biosynthesized .sup.14 C-cholesterol in
test runs and in "solvent control". The external standard was mevinolin
sodium salt. The IC.sub.50 and IC.sub.70 values (IC.sub.50 or IC.sub.70 is
the molar (mol/liter) concentration of the compound which is necessary for
a 50 or 70% inhibition) varied somewhat for different test batches. The
mean values for mevinolin sodium salt were IC.sub.50 =5.times.10.sup.-8 M
and IC.sub.70 =1.5.times.10.sup.-7 M. The measured ICs for test compounds
(sodium salts of the dihydroxycarboxylic acids of the formula II) (Table
2) were corrected by the deviation of mevinolin sodium from its mean
value. Mevinolin sodium was assigned a relative potency of 100.
TABLE 2
______________________________________
Relative
potency
IC.sub.50 (M)
IC.sub.70 (M)
in %
______________________________________
Standard 5.0 .times. 10.sup.-8
1.5 .times. 10.sup.-7
100
mevinolin
sodium salt
Compound C 2.7 .times. 10.sup.-8
7 .times. 10.sup.-8
185 (214)
Example
1 4.3 .times. 10.sup.-9
.sup. .about.8 .times. 10.sup.-10
1163
(18750)
2 2.2 .times. 10.sup.-9 2273
3 3.8 .times. 10.sup.-9 1316
4 8.0 .times. 10.sup.-9 625
5 9.2 .times. 10.sup.-9 543
6 1.7 .times. 10.sup.-6 3
7 9.2 .times. 10.sup.-7 5
8 4.0 .times. 10.sup.-9 1250
9 7.5 .times. 10.sup.-9
1.2 .times. 10.sup.-8
667 (1250)
______________________________________
3) Action on serum lipoproteins and other metabolic parameters of male rats
in the subchronic test
Method:
Groups of male rats of the strain HOE: WISKf (SPF 71) having a starting
weight of above 180 g received the test preparations daily in the morning
(sodium salts of the dihydroxycarboxylic acids of the formula II) in
polyethylene glycol 400 by stomach tube; the respective control group
received only the vehicle. The last (7th) administration was carried out
24 hours before taking blood and sacrificing. There was free access to
food and water during the experiment. 24 hours before taking blood, which
wall carried out retroorbitally under slight ether anesthesia before and
after the treatment period (i.e. on the 1st and 8th day), the food was
withdrawn. Total cholesterol was determined in the serum of each
individual animal [CHODPAP high performance method of Boehringer
Mannheim], and, as a measure of the triglycerides, total glycerol was also
determined analytically from the serum pool of all the animals of one
group [GPO-PAP high performance method, Boehringer Mannheim].
Immediately after taking blood, the animals were sacrificed by dislocation
of the spine, and the relative liver weight, the change in body weight and
the food consumption were determined.
For the analysis of the serum lipoproteins, the serum of all the rats of
one group was pooled. The serum lipoproteins were separated using the
preparative ultracentrifuge.
The following conditions were used for the separation of the fractions
VLDL, LDL and HDL:
______________________________________
1. VLDL density <1.006
2. LDL density 1.006 to 1.04
3. HDL density 1.04 to 1.21
4. Subnatant of the HDL
density >1.21
.sup. (VHDL)
______________________________________
The determination of the protein was carried out by the method of Lowry et
al. [LOWRY O. H., ROSEBOROUGH, N.J., PARR, A. L. and RANDELL, R. J.: J.
Biol. Chem. 193, 265 (1951)].
TABLE 3
__________________________________________________________________________
% changes in the mean value
Relative to
% change compared to control
control Relative to
Test substance
Dose
Total cholesterol
Protein
Glycerol
Liver
Food starting
Cholesterol
Example mg/kg
VLDL
LDL
HDL VLDL
LDL
VLDL weight
consumption
Body weight
HDL/LDL*
__________________________________________________________________________
7 100 -23 -52
+9 -15 -8 -3 -1 .+-.0 +5 2.25
6 100 +13 -16
-3 -2 +3 -8 +1 -1 +5 1.15
6 30 +12 -26
+13 -4 -24
+8 +3 -1 +5 1.27
Standard clofibrate
100 -40 -19
-29 -16 -9 +4 +15
+1 +8 0.88
Standard probucol
30
+4 -24
-11 -6 -23
+24 +5 .+-.0 +5 0.97
None (control)
-- -- -- -- -- -- -- -- -- +4 1.00*
__________________________________________________________________________
*Control standardization to 1.00
4) Hypocholesterolemic activity in rabbits after p.o. administration
Normolipemic male white New Zealand rabbits, body weight 3-3.5 kg, were
divided into groups of 5 animals. The groups in each case received one of
the test compounds (sodium salts of the compounds of the formula II),
suspended in 1% aqueous methylcellulose (.RTM.Tylose MH 300), 5.10 or 20
mg/kg/day daily in the morning by stomach tube. The animals of the control
groups received only Tylose MH 300. Every 3-4 days samples of venous blood
were taken from all animals 20 hours after the oral administration. The
serum total cholesterol was determined enzymatically in these samples
using the test combination of Boehringer Mannheim (CHOD-PAP high
performance method). The serum cholesterol level of the treated animals
was compared with that of the control groups. A "discharge phase" followed
the 20-day "treatment phase", in which the change in the serum cholesterol
level was further monitored.
Before, three times during the treatment phase and in the discharge phase,
the safety parameters (SGOT, SGPT, aP, bilirubin and creatinine in the
serum) of the animals in the control group and in the treated groups were
also determined. They showed no significant changes.
Before, six times during the treatment phase and in the discharge phase,
the body weight of the animals in the control group and in the treated
groups was also determined. No significant change took place compared to
the starting (.+-.1%) .
__________________________________________________________________________
Serum total cholesterol
% change compared to control group
Test Dose Number of administration
Discharge phase
compound
mg/kg per day
3 10 14 17 20 3 6 11 22
__________________________________________________________________________
Ex. 1 5 mg (constant)
-44
-46
-43
-42
-48
-22
-17
-6 --
Ex. 9 5 mg (constant)
-8 -12
-15
-- -- -4 -4 +6 --
Compound C
10 mg (up to
+7 -32
10th day)
20 mg (from -31
-37
-36
-13
-23
-16
+18
11th day)
Mevinolin
10 mg (up to
-12
-30
10th day)
20 mg (from -27
-24
-26
+14
-1 +2 0
11th day)
__________________________________________________________________________
From Table 4, it can be seen that the compound from Example 1 causes a
substantially greater plasma cholesterol decrease than mevinolin or the
compound C in spite of lower dosage. Furthermore, it can be seen that the
action of the compound from Example 1 commences very early on. The maximum
action was virtually achieved even in the first measurement after 3 days
of treatment.
5) Inhibition of microsomal lipid peroxidation (in vitro)
The inhibition of lipid peroxidation was measured under the experimental
conditions described by H. Wafers and H. Sies, Eur. J. Biochem. 174,
353-357 (1988). The microsomes were obtained according to the literature
cited therein. IC.sub.50 denotes the concentration of the test compound in
moles per liter which causes a 50% inhibition of lipid peroxidation.
TABLE 5
______________________________________
Process/ Inhibition at
Example Example IC.sub.50 10.sup.-5 mol/l
______________________________________
4 4.4 .times. 10.sup.-6
90%
5 -- 11%
6 3.0 .times. 10.sup.-6
95%
7 4.0 .times. 10.sup.-6
92%
8 -- 1%
12 1.5 .times. 10.sup.-6
99%
22 1.6 .times. 10.sup.-6
99%
23 2.8 .times. 10.sup.-6
98%
25 4.8 .times. 10.sup.-6
83%
1 -- <10%
2 -- <10%
5 -- 0%
6 2.7 .times. 10.sup.-6
98%
7 -- <10%
8 -- 27%
9 -- <10%
______________________________________
6) Inhibition of Cu.sup.2+ -catalyzed LDL oxidation in vitro LDL was
isolated from porcine plasma which contained EDTA (1 mg/ml) by
ultracentrifugation in salt solutions of NaCl/NaBr between the densities
1.019 and 1.063 g/ml (cf. R. J. Havel et al., J. Clin. Invest. 43, 1345
(1955)). LDL was then dialyzed against phosphate-buffered saline (160 mM
NaCl, 10 mM NaH.sub.2 PO.sub.4), pH 7.4 and stored under nitrogen at
4.degree. C. Before the oxidation process, the LDL fractions were diluted
to a final protein concentration of 0.1 mg/ml using phosphate-buffered
saline and 2.5 ml aliquot parts were pre-incubated under nitrogen with the
test compounds (25 .mu.l of ethanolic solution) for 1 hour at 37.degree.
C. (cf. McLean et al., Biochemistry 1989, 28, 321). For the Cu.sup.2+
-catalyzed oxidation of LDL, 12.5 .mu.l of a 1 mM CuSO.sub.4 solution were
added to each sample, a 5 .mu.M Cu.sup.2+ concentration resulting. The
incubation was carried out for 2 hours at 37.degree. C. and in an air
atmosphere. The fluorescence intensity was measured at 430 nm (excitation
wavelength 365 nm) (cf. Steinbrecher, U. P., J. Biol. Chem. 1987, 262,
3603). The IC.sub.50 value (concentration of the test compound in mol per
liter which causes a 50% inhibition of LDL oxidation) was determined from
the decrease in the relative fluorescence intensity (LDL.sub.OX =100). The
values are compiled in Table 6. In addition, the inhibition using a
10.sup.-5 N concentration of the test compound is indicated in %.
TABLE 6
______________________________________
Process IC.sub.50
Inhibition at
Example Example .mu.mol/l
10.sup.-5 M
______________________________________
6 1.0
25 0.15
1 >10 41%
8 1.1
9 6.0
10 >10 23%
Standard 0.50
probucol
______________________________________
In the following process examples, the synthesis of precursors which are
required for the preparation of the compounds of the formulae I and II
according to the invention is described. In the examples, the preparation
of compounds of the formulae I and II according to the invention, their
esters and salts is described. The process examples and the examples do
not have a limiting character on the scope of the invention.
General Experimental Technique
Reactions were carried out in glass apparatuses under a nitrogen inert gas
atmosphere. If not stated otherwise, technical-grade solvents were used
for reactions and chromatography without further purification or drying.
Reagents had a purity of at least 97% (usually >99%). Drying of reaction
extracts was carried out, if not stated otherwise, with magnesium sulfate.
Thin-layer chromatographic analyses (TLC) were carried out on prepared
silica gel 60 glass TLC plates containing fluorescent indicator F.sub.254
(Merck). The detection of the product spots was carried out by means of
UV, and by the use of spray reagents for staining.
Column chromatographic separations were carried out in glass columns and
under conditions such as have been described for flash chromatography [W.
C. Still et al., J. Org. Chem. 43, 2923 (1978)]. Silica gel of particle
size 35-70 Mm, pore diameter 60 .ANG. or 70-200 .mu.m, pore diameter 60
.ANG. from Amicon, was used.
.sup.1 H-NMR spectra were recorded using a .RTM.Bruker WP60 or WM270
spectrometer. If not stated otherwise, CDCl.sub.3 was used as the solvent.
Chemical shifts are indicated in ppm, relative to tetramethylsilane as
internal standard.
Mass spectra were recorded using a .RTM.Kratos MS9 (FAB) or MS80 (CI)
spectrometer.
Melting points were determined using a Buchi capillary melting point
apparatus (according to Dr. Tottoli) and are uncorrected.
PROCESS EXAMPLE 1
2-Bromo-6-isopropylphenol (scheme 1, formula Viii)
198.1 ml (3.85 mol) of bromine were added dropwise at -5.degree. to
0.degree. C. to a solution of 470 g of sodium hydroxide in 2 l of water.
The mixture was stirred at this temperature for a further 10 min. The
resulting sodium hypobromite solution was added dropwise at -5.degree. to
0.degree. C. to a solution of 464 g of a 40% strength aqueous
dimethylamine solution (4.11 mol) in 50 ml of water. The mixture was
stirred for a further 30 min, the organic phase was then separated off and
the aqueous phase was extracted twice using 750 ml of methylene chloride
each time. The combined organic phases were dried briefly over magnesium
sulfate and filtered. The filtrate was added dropwise at -10.degree. C. to
a solution of 500 g (3.67 mol) of ortho-isopropylphenol in 900 ml of
methylene chloride. After adding about 2/3 of the filtrate, a solid formed
and the reaction mixture became viscous and could only be stirred with
difficulty. 500 ml of methylene chloride were added at -10.degree. C. and
the mixture was stirred for a further hour. The solid was filtered off
with suction, washed with a little cold methylene chloride, suspended in
1.5 1 of 2N sulfuric acid and stirred at room temperature until all the
solid had been converted into an oil. The organic phase was separated off,
and the aqueous phase was extracted using methylene chloride. The combined
organic phases were washed with sodium chloride solution and dried, and
the solvent was removed in vacuo. The residue was distilled through a 30
cm Vigreux column in a water jet vacuum.
391.7 g (1.82 mol) of colorless oil, b.p. 122.degree.-124.degree. C./21
torr; yield 49.6%
NMR (60 MHz): .delta.=1.20 (d, 6H, CH.sub.3), 3.23 (sept., 1H, CH), 5.42
(s, 1H, OH), 6.4-7.2 (m, 3H, arom. H).
PROCESS EXAMPLE 2
2-(p-Fluorophenyl)-6-isopropylphenol (scheme 1, formula IX)
a) Three iodine crystals were added to 18.7 g (0-77 mol) of magnesium
turnings and the site of addition was heated with a hot air apparatus
(.RTM.Fon) until iodine vapor was visible in the flask. The mixture was
cooled to room temperature and 20 ml of absolute THF were added. 131.3 g
(0.75 mol) of p-bromofluorobenzene were poured into a 500 ml dropping
funnel and about 2 ml thereof were added to the reaction flask. The brown
color of the reaction mixture rapidly disappeared and strong evolution of
heat took place to reflux. A further 50 ml of absolute THF were
immediately added to the reaction mixture and the p-bromofluorobenzene in
the dropping funnel was diluted with 200 ml of THF. This solution was then
added dropwise in such a way that a gentle reflux was maintained. The
reaction mixture was subsequently boiled under reflux for a further hour
and then cooled to 50.degree. C.
b) In a second flask, the dissolved oxygen was driven off from the solution
of 52.0 g (0.24 mol) of 2-bromo-6-isopropylphenol in 150 ml of absolute
THF by means of introducing nitrogen for 20 minutes. 1.7 g (1.5 mmol) of
tetrakis(triphenylphosphine)palladium(O) were added with minimization of
oxygen contact.
The Grignard solution from step a) was then transferred to this solution
under nitrogen pressure by means of a double needle (".RTM.Flex-Needle",
Aldrich), evolution of heat occurring. The speed of the transfer was
chosen so that a gentle reflux was maintained. The mixture was
subsequently heated to reflux for a further 6 hours. The reaction mixture
was cooled and poured onto 500 g of ice/100 ml of conc. hydrochloric acid.
The organic phase was separated off and the aqueous phase was extracted
using 3.times.100 ml of ether. The combined organic phases were washed
with 100 ml of saturated sodium chloride solution and dried, and the
solvent was stripped off. The residue was distilled through a 30 cm
Vigreux column under a pump vacuum. After a forerun (30.degree.-65.degree.
C./0.2 torr), the pure product distilled (b.p. 107.degree.-109.degree.
C./0.5 torr) as a colorless oil which crystallized in the receiver and
partly also even in the distillation bridge (m.p. 44.degree.-46.degree.
C.). In order to avoid blocking of the bridge, this was
temperature-controlled to about 50.degree. C. Yield 37.8 g of title
compound (164 mmol); 68.4% of theory. GC analysis (30 m fused silica
column DB-5 "polydiphenyldimethylsiloxane", layer thickness 0.25 .mu.m,
internal diameter 0.32 m, 180.degree. C., injector 240.degree. C., 1 bar
of H.sub.2): t.sub.ret : 4.46 min; purity>99.9%.
NMR (270 MHz): .delta.=1.28 (d, 6H, CH.sub.3 ) 3.32 (sept., 1H, CH), 5.08
(s, 1H, OH), 6.9-7.5 (m, 7H, arom. H).
MS (DCI, isobutane): m/e=231 (M+H.sup.+), 230 (M.sup.+), 215 (M.sup.+
--CH.sub.3),
PROCESS EXAMPLE 3
2-(p-Fluorophenyl)-4-thiocyanato-6-isopropylphenol (scheme 1, formula X)
A suspension of 70.9 g (838 mmol, 5.0 equivalents) of sodium thiocyanate in
200 ml of methanol was stirred at room temperature for 20 min. 40.0 9
(173.8 mmol, 1.0 equiv.) of 2-(p-fluorophenyl)-6-isopropylphenol were
added and the mixture was stirred for 20 minutes. 14.32 ml (277.8 mmol,
1.6 equiv.) of bromine were dissolved in 50 ml of methanol (exothermic)
and this solution was added dropwise at 15.degree.-20.degree. C. to the
above reaction solution during the course of 20 minutes. The reaction
mixture turned yellow and the phenol dissolved completely. The reaction
mixture was stirred for 30 min. TLC (toluene/cyclohexane 1:1) showed
complete conversion of the starting material (R.sub.f =0.54). In addition
to the title compound (R.sub.f =0. 32), only a small amount of the
corresponding para-bromo compound, which cochromatographed with the
starting material (R.sub.f =0. 54), was obtained as an impurity, but was
able to be differentiated owing to different coloration. The reaction
mixture was poured onto 400 g of ice/400 ml of 2N hydrochloric acid and
extracted using 4.times.200 ml of toluene. The extracts were washed with
aqueous sodium sulfite solution, filtered, washed with saturated sodium
chloride solution, dried and concentrated in vacuo.
The yellow solid which remained was dissolved in 500 ml of hot cyclohexane
and 5 g of active carbon were added. The mixture was then heated under
reflux for 5 minutes and the hot suspension was filtered in vacuo. The
active carbon filtered off with suction was subsequently washed with 20 ml
of hot cyclohexane. The almost colorless filtrate cooled slowly and was
then cooled to 10.degree. C. for a further 12 hours.
The colorless crystals (title compound) were filtered off with suction and
dried in vacuo. 47.6 g (165.7 mmol) yield corresponding to 95.3%; m.p.:
94.5.degree.-96.degree. C.
NMR (60 MHz): .delta.=1.26 (d, 6H, CH.sub.3), 3.32 (sept., 1H, CH), 5.46
(s, 1H, OH), 7.0-7.6 (m, 6H, arom. H).
MS (DCI, isobutane): m/e=288 (M+H.sup.+), 272 (M.sup.+ --CH.sub.3), 261
(M.sup.+ --CN)
PROCESS EXAMPLE 4
2-(P-Fluorophenyl)-4-mercapto-6-isopropylphenol (scheme 1, formula III/2)
A solution of 32.5 g (113 mmol) of
2-(p-fluorophenyl)-4-thiocyanato-6-isopropylphenol in 150 ml of absolute
THP was added dropwise to a suspension of 7.5 g (198 mmol) of lithium
aluminum hydride in 20 ml of absolute THF. The reaction mixture was heated
under reflux for 90 min. TLC (CH/EA 9:1; R.sub.f of the thiocyanate: 0.16;
R.sub.f of the mercaptan: 0.26) indicated quantitative reaction. 100 ml of
conc. hydrochloric acid were cautiously added dropwise to the mixture with
dry ice-cooling. The aluminum salts went into solution during the course
of this. The reaction mixture was extracted several times with ether. The
combined extracts were washed with saturated sodium chloride solution and
dried, and the solvents were removed in vacuo. The residue was filtered
through a silica gel column under nitrogen pressure using the above
eluent. 27.3 g (104 mmol) of the pure product (title compound) were
obtained as a colorless oil (yield: 92.1%).
NMR (60 MHz): .delta.=1.27 (d, 6H, CH.sub.3), 3.30 (sept., 1H, CH), 3.40
(s, 1H, SH), 5.06 (s. 1H. OH), 6.93-7.63 (m, 6H, arom. H).
MS (DCI, isobutane) : m/e=262 (M.sup.+), 247 (M.sup.+ --CH.sub.3).
IR (CHCl.sub.3): 3555 (OH), 2560 (weak, SH), 1510, 1455, 1223, 840
cm.sup.-1.
The product is sensitive to oxidation and must be handled with rigorous
exclusion of oxygen.
PROCESS EXAMPLE 5
4,4-(Isopropylidenedithio)-bis-[(2-isopropyl-6-p-fluorophenyl)phenol]
(scheme 1, formula III/3)
27.3 g (104 mmol) of 2-(p-fluorophenyl)-4-mercapto-6-isopropylphenol were
dissolved in 100 ml of benzene which had been previously freed of oxygen
by means of bubbling nitrogen through. 13.5 g (16 ml, 130 mmol) of
2,2-dimethoxypropane, followed by about 100 mg (.about.0.5 mmol) of
p-toluenesulfonic acid monohydrate were added. The reaction mixture was
stirred at room temperature for 30 min, then under reflux for 8 hours. It
was washed with aqueous sodium acetate solution, then with saturated
sodium chloride solution, dried and concentrated in vacuo. The oil which
remained (29.0 g) was chromatographed on silica gel using
cyclohexane/toluene 1:1+1 part per thousand triethylamine and gave 26.0 g
of title compound (46.0 mmol, yield 88.5%) as a yellowish oil which
crystallized in the refrigerator. It melted close to room temperature.
NMR (60 MHz): .delta.=1.28 (d, 12H, C(CH.sub.3).sub.2), 1.53 (s, 6H,
--S--C(CH.sub.3).sub.2 --S), 3.32 (sept., 2H, CH), 5.26 (s,, 2H, OH),
7.0-7.7 12H, arom. H)
MS (FAB, 3-NBA/LiI): m/e571 (M+Li.sup.+), 303
##STR27##
PROCESS EXAMPLE 6
2-(p-Fluorophenyl)-4-(p-fluorophenylthio)-6-isopropylphenol (scheme 1,
formula III/1)
A THF solution (100 ml) of p-fluorophenylmagnesium bromide [from 3.11 9
(128 mmol) of magnesium and 22.0 g (13.8 ml, 126 mmol) of
p-bromofluorobenzene] was prepared as in Process Example 2. A solution of
6.04 g (21 mmol) of 2-(p-fluorophenyl)-4-thiocyanato-6-isopropylphenol
(from Process Example 3) in 50 ml of THF was added dropwise at 50.degree.
C. and stirred at 40.degree.-50.degree. C. for a further 2 hours. The
mixture was cooled and poured onto 500 ml of ice-cold 2N hydrochloric
acid. The mixture was extracted three times using 200 mi of ether. The
combined extracts were washed with sodium chloride solution and dried, and
the solvent was removed in vacuo.
The oil which remained (title compound) (7.5 g, 21 mmol, yield.about.100%)
was pure according to TLC (cyclohexane/ethyl acetate 9:1) and .sup.1
H-NMR.
NMR (60 MHz): .delta.=1.25 (d, 6H, CH.sub.3), 3.31 (sept., 1H, CH), 5.22
(s, 1H, OH), 6.8-7.8 (m, 10H, arom. H).
MS (DCI, isobutane): m/e=357 (M+H.sup.+), 356 (M.sup.+).
PROCESS EXAMPLE 7
2-(p-Fluorophenyl)-4-(phenylthio)-6-isopropylphenol (scheme 1, formula
III/1)
In analogy to Process Example 6, the action of 6 equivalents of
phenylmagnesium bromide on
2-(p-fluorophenyl)-4-thiocyanato-6-isopropylphenol (from Process Example
3) in THF at 40.degree.-50.degree. C. gave the title compound in 95%
yield.
NMR (60 MHz): .delta.=1.25 (d, 6H, CH.sub.3) 3.30 (sept., 1H, CH), 5.20 (s,
1H, OH), 6.9-7.8 (m, 11H, arom. H).
MS (DCI, isobutane): m/e=339 (M+H.sup.+), 338 (M.sup.+).
PROCESS EXAMPLE 8
2-(p-Fluorophenyl)-4-(isopropylthio)-6-isopropylphenol (scheme 1, formula
III/1)
910 mg (39.6 mmol) of sodium pieces were added to 20 ml of isopropanol and
the mixture was stirred until the metal had completely disappeared. A
solution of 2.5 g (8.7 mmol) 3) of
2-(p-fluorophenyl)-4-thiocyanato-6-isopropylphenol (from Process Example
3) in 50 ml of isopropanol was added dropwise to the solution obtain
during the course of one hour. The reaction mixture was heated under
reflux for 30 min, then poured into 100 ml of 2N sulfuric acid and
extracted using 3.times.100 ml of ether. The combined extracts were washed
with saturated sodium chloride solution, dried and concentrated in vacuo.
The oil residue (2.42 g) was chromatographed using cyclohexane/ethyl
acetate 2:1, later 1:1 and yielded 640 mg (2.1 mmol, yield 24.1%) of a
viscous, yellowish oil (title compound).
NMR (60 MHz): .delta.=0.97 (d, 6H, SC(CH.sub.3).sub.2), 1.20 (d, 6H,
C(CH.sub.3).sub.2)3.00-3.90 (2 x sept., 2H, CH), 5.20 (s, 1H, OH), 6.9-7.7
(m, 6H, arom. H).
MS (DCI, isobutane): m/e=305 (M+H.sup.+), 304 (M.sup.+).
PROCESS EXAMPLE 9
2-Bromo-6-cyclopropylphenol (scheme 1, formula VIII)
In analogy to Process Example 1, the title compound was obtained from
ortho-cyclopropylphenol [Y. S. Shaborov, V. K. Potapov and R. Y. Levina,
J. Gen. Chem. USSR 34, 3171 (1964)]in 384 yield as a colorless oil.
NMR (60 MHz): .delta.=0.73 (m, 4H, CH.sub.2), (qui, 1H, CH), 5.42 (s, 1H,
OH), 6.4-7.2 (m, 3H, arom. H).
MS (DCI, isobutane): m/e=213/215 (M+H.sup.+), 212/214 (M.sup.+).
PROCESS EXAMPLE 10
2-(p-Fluorophenyl)-6-cyclopropylphenol (scheme 1, formula IX)
In analogy to Process Example 2, the title compound was obtained from
2-bromo-6-cyclopropylphenol in 47% yield as a colorless solid.
NMR (60 MHz): .delta.=0.78 (m, 4H, CH.sub.2), 1-85 (qui, 1H, CH), 5.00 (s,
1H, OH), 6.7-7.5 (m, 7H, arom. H).
MS (DCI, isobutane): m/e=229 (M+H.sup.+), 228 (H.sup.+).
PROCESS EXAMPLE 11
2-(p-Fluorophenyl)-4-thiocyanato-6-cyclopropylphenol (scheme 1, formula X)
In analogy to Process Example 3, the title compound was obtained from
2-(p-fluorophenyl)-6-cyclopropylphenol in 62% yield as a pale yellow solid
(m.p. 82.degree.-85 0c).
NMR (60 MHz): .delta.=0.79 (m, 4H, CH.sub.2), 1.88 (qui, 1H, CH), 5.36 (B,
1H, OH), 6.9-7.6 (m, 6H, arom. H).
MS (DCI, isobutane): m/e=286 (M+H.sup.+), 259 (M.sup.+ --CN).
PROCESS EXAMPLE 12
2-(p-Fluorophenyl)-4-(p-fluorophenylthio)-6-cyclopropylphenol (scheme 1,
formula III/1)
In analogy to Process Example 6. the title compound was obtained from
2-(p-fluorophenyl)-4-thiocyanato-6-cyclopropylphenol as a viscous, pale
yellow oil.
NMR (60 MHz): .delta.=0.78 (m, 4H, CH.sub.2), 1.87 (qui, 1H, CH), 5.12 (s,
1H, OH), 6.7-7.7 (m, 10H, arom. H).
MS (DCI, isobutane): m/e=355 (M+H.sup.+), 354 (M.sup.+).
PROCESS EXAMPLE 13
2-(p-Fluoro-m-methylphenyl)-6-isopropylphenol (scheme 1, formula IX)
In analogy to Process Example 2, the title compound was obtained from
2-bromo-6-isopropylphenol (from Process Example 1) and the Grignard
reagent from p-fluoro-m-methylbromobenzene in 68% yield as a colorless
solid.
NMR (60 MHz): .delta.=1.25 (d, 6H, CH.sub.3), 2.35 (s, 3H, CH.sub.3), 3.30
(sept., 1H, CH), 5.00 (s, br, 1H, OH), 6.7-7.5 (m, 6H, arom.
MS (DCI, isobutane): m/e=245 (M+H.sup.+), 244 (M.sup.+), 229 (M.sup.+
--CH.sub.3).
PROCESS EXAMPLE 14
2-(p-Fluoro-m-methylphenyl)-4-thiocyanato-6-isopropylphenol (scheme 1,
formula X)
In analogy to Process Example 3, the title compound was obtained from
2-(p-fluoro-m-methylphenyl)-6-isopropylphenol in a 59% yield as a pale
Yellow solid (m.p. 96.degree.-98.degree. C.).
NMR (60 MHz): .delta.=1.26 (d, 6H, CH.sub.3), 2.35 (s, 3H, CH.sub.3), 3.32
(sept., 1H, OH), 5.47 (s, 1H, OH), 7.0-7.6 (m, 5H, arom. H).
MS (DCI, isobutane): m/e=302 (M+H.sup.+), 286 (M.sup.+ --CH.sub.3), 275
(M.sup.+ --CN).
PROCESS EXAMPLE 15
2-(p-Fluoro-m-methylphenyl)-4-(p-fluorophenylthio) -6-isopropylphenol
(scheme 1, formula III/1)
In analogy to Process Example 6, the title compound was obtained from
2-(p-fluoro-m-methylphenyl)-4-thiocyanato-6-isopropylphenol as a viscous,
pale yellow oil.
NMR (60 MHz): .delta.=1.25 (d, 6H, CH.sub.3), 2.34 (s, 3H, CH.sub.3), 3.31
(sept., 1H, CH), 5.23 (s, 1H, OH), 6.8-7.8 (m, 9H, arom. H).
MS (DCI, isobutane): m/e=371 (M+H.sup.+), 370 (M.sup.+).
PROCESS EXAMPLE 16
1-Acetyl-2,5-diisopropylbenzene (scheme 3, formula XIV)
A solution of 142 ml (157 g, 2.0 mol) of acetyl chloride in 362 ml (310 g,
1.91 mol) of 1,4-diisopropylbenzene was added dropwise during the course
of 2 hours to a suspension of 200 g (1.5 mol) of aluminum trichloride in
260 ml of carbon disulfide cooled to -10.degree. C. The mixture was
stirred for a further 1.5 hours at -100.degree. C., in the course of which
the evolution of hydrogen chloride greatly decreased, and a further 100 g
(0.75 mol) of aluminum trichloride were then added in portions and the
mixture was stirred for a further hour. The reaction mixture was
cautiously poured onto I kg of ice/100 ml of 2N hydrochloric acid
(strongly exothermic? ). The oily organic phase was separated off and the
aqueous phase was extracted twice using ether. The combined organic phases
were washed with dilute sodium carbonate solution, then with water and
dried over calcium chloride. The solvents were stripped off and the
residue was distilled through a 30 cm Vigreux column in a pump vacuum.
After a forerun (b.p. 70.degree.-91.degree. C./ 0.6 torr, colorless oil,
10.9 g), the title compound (b.p. 92.degree.-95.degree. C./0.6 torr,
colorless oil, 344.3 g, 1.69 mol), was obtained, yield 88.4%. The afterrun
(b.p. 97.degree.-104.degree. C./1.0 torr, 10.25 g) is a colorless oil
which immediately solidifies.
The product is pure according to TLC (cyclohexane/ethyl acetate 5:1,
R.sub.f =0.45).
PROCESS EXAMPLE 17
1-(2-Hydroxy-2-propyl)-2,5-diisopropylbenzene (scheme 3, formula XV)
197 g (0.97 mol) of 1-acetyl-2,5-diisopropylbenzene were added dropwise to
468 ml (1.4 mol) of a commercial 3-molar solution of methylmagnesium
iodide in ether in such a way that a gentle reflux was maintained. The
mixture was heated under reflux for a further one hour, then poured
cautiously onto 1.5 l of ice-cold, aqueous ammonium chloride solution, and
the organic phase was separated off and extracted twice more using ether.
The combined organic phases were washed with saturated sodium chloride
solution and dried, and the solvent was removed in vacuo.
213.1 g (yield 100%) of a viscous oil (TLC: cyclohexane/ethyl acetate 5:1,
R.sub.f =0.26) were obtained. Pure 1-(2-
hydroxy-2-propyl)-2,5-diisopropylbenzene can be obtained from this crude
product by crystallization from about 400 ml of petroleum ether at
-20.degree. C. The crystal formation frequently requires several days.
NMR (60 MHz): .delta.=1.25 (d, 12H, CH.sub.3), 1.68 (s, 6H, CH.sub.3), 1.74
(s, 1H, OH), 2.86 (sept., 1H, CH), 3.82 (sept., 1H, CH), 6.96-7.42 (m, 3H,
arom. H).
It is advantageous to react the crude alcohol further directly.
PROCESS EXAMPLE 18
1,2,5-Triisopropylbenzene (scheme 3, formula XVII)
The crude alcohol from Process Example 17 (213.1 g, 0.97 mol) was heated
under reflux in a water separator with 800 ml of toluene and two spatula
tips full of paratoluenesulfonic acid hydrate. 15 ml of water were
separated in the course of 1 hour. TLC (100% toluene) showed complete
reaction of the alcohol (R.=0.17) to the olefin (R.sub.f =0.79). The
toluene was removed in vacuo at a bath temperature of 20.degree. C. The
oily residue was dissolved in 160 ml of n-hexane. 4.7 g of 10% palladium
on carbon were added under nitrogen and the mixture was shaken at room
temperature under a hydrogen atmosphere of 1 atm. 21.2 l of hydrogen were
absorbed in the course of 12 hours. The catalyst was filtered off with
suction through kieselguhr (for example .RTM.Celite) and washed with
n-hexane. The filtrate was concentrated in vacuo at a bath temperature of
20.degree. C. The oily residue was distilled through a 30 cm Vigreux
column in a water jet vacuum. The distillate in the boiling range
70.degree.-128.degree. C./12 torr (178.5 g) was collected in fractions.
All fractions contained the product (R.sub.f =0.65) according to TLC
analysis (100% cyclohexane) in addition to a polar impurity (R.sub.f
=0.05), the content of which increased with progressive distillation. The
impurity was removed by column chromatography (100% cyclohexane).
166.2 g (0.81 mol) of the title compound were obtained as a colorless oil.
Yield 83.8%.
NMR (60 MHz): .delta.=1.18 (d, 18H, CH.sub.3), 2.63-3.60 (3 x sept., 3H,
CH), 6.87-7.30 (m, 3H, arom. H).
MS (DCI, isobutane): m/e=205 (M+H.sup.+), 204 (M.sup.+), 189 (M.sup.+
--CH.sub.3).
GC (30 m fused silica column DB-5 "polydiphenyldimethylsiloxane", layer
thickness 0.25 .mu.m, internal diameter 0.32 mm, 160.degree. C., injector
240.degree. C., 1 bar of helium): t.sub.ret 4.39 min, purity 97.1%.
PROCESS EXAMPLE 19
1-Bromo-2,4,5-triisopropylbenzene (scheme 3, formula XVIII)
A spatula tip full of iron powder was added at -10.degree. C. to a solution
of 301.3 g (1.47 mol) of 1,2,5-triisopropylbenzene in 600 ml of carbon
tetrachloride and a solution of 76 ml (236.2 g, 1.48 mol) of bromine in
600 ml of carbon tetrachloride was then added dropwise with rigorous
exclusion of light. Initially, no noticeable evolution of hydrogen bromide
took place and the bromine color of the reaction solution remained. After
complete addition, the mixture was allowed to warm to 0.degree. C.,
whereupon a vigorous evolution of hydrogen bromide commenced. The mixture
was stirred for a further 90 min At room temperature, after which TLC
(100% cyclohexane) indicated extensive disappearance of the starting
material (R.sub.f =0.51) (product R.sub.f =0.57; by-product R.sub.f
=0.64).
The reaction solution was partitioned between methylene chloride and 10%
strength sodium thiosulfate solution. The organic phase was separated off
and the aqueous phase was extracted once more with methylene chloride. The
combined organic phases were washed with sodium chloride solution, dried
and concentrated in vacuo. The oily residue was fractionated through a 20
cm Vigreux column in a pump vacuum:
1) forerun, 5.3 g of colorless oil, b.p. 71.degree.-103.degree. C./1 torr
2) main run, 265.4 g (0.94 mol) of the title compound, b.p.
105.degree.-112.degree. C./1 torr, very pale yellow oil, yield 64.0%
3) after-run 35.8 g of yellow oil, b.p. 114.degree.-120.degree. C./1 torr,
title compound+by-product.
GC of the main run (column DB-5, conditions as in Process Example 18):
t.sub.ret 8.81 min, purity: 98.4%.
NMR (60 MHz) 1.24 (d, 18H, CH.sub.3 3.19 (sept., 1H, CH), 7.12 (s, 1H,
arom. H), 7.33 (s, 1H, arom. H).
MS (PCI, isobutane): m/e=285/283 (M+H.sup.+), 284/282 (M.sup.+), 269/267
(M.sup.+ --CH.sub.3), 243/241 (M.sup.+ --.LAMBDA..)
PROCESS EXAMPLE 20
1-(p-Fluorophenyl)-2,4,5-triisopropylbenzene (scheme 3, formula XIX)
A few crystals of iodine were added to 22.3 g (0.92 mol) of magnesium
turnings and the mixture was heated using a hot air apparatus (.RTM.Fon)
until violet iodine vapor was formed. About 50 ml of absolute THF were
added, followed by about 20 ml of a total of 251 g (0.89 mol) of
1-bromo-2,4,5-triisopropylbenzene. As soon as the reaction had started
(heating to reflux may be necessary), 150 ml of absolute THF were added
through the reflux condenser, the residual bromine compound was diluted in
the dropping funnel with about 300 ml of THF and this solution was added
dropwise in such a way that a gentle reflux was maintained. After complete
addition, the mixture was heated for a further 30 min under reflux and a
clear, slightly greenish solution was obtained, which was cooled to about
40.degree. C.
In a second apparatus, the oxygen was driven out of a solution of 162.6 g
(0.93 mol) of 4-bromofluorobenzene in 800 ml of absolute THF by bubbling
nitrogen through (30 min). 10 g (8.6 mmol) of
tetrakis(triphenylphosphine)palladium(O) were added and the solution was
stirred at room temperature for 10 min. The above Grignard solution was
then transferred to this solution under pressure by means of a double
needle using nitrogen (about 15 min). The mixture was heated under reflux
for 2 hours, whereupon a white precipitate deposited from the initially
clear reaction solution. The reaction mixture was allowed to cool and
poured into ether and 2N hydrochloric acid, the precipitated magnesium
bromide being largely removed by decanting. The organic phase was
separated off and washed successively with 2N hydrochloric acid, water,
saturated sodium hydrogen carbonate solution and saturated sodium chloride
solution, then dried, filtered and concentrated in vacuo.
The residue was distilled in a pump vacuum without a column and using a
short, air-cooled bridge. After a forerun (25.5 g, b.p.
25.degree.-101.degree. C./0.15 torr), the product (187.5 g, 628 mmol, b.p.
114.degree. C./0.05 torr) distilled and immediately crystallized to give a
colorless, hard solid (title compound) (m.p. 75.degree.-78.degree. C.).
NMR (60 MHz): .delta.=1.10-1.36 (3 xd, 18H, CH.sub.3)2.80-3.56 (m, 3H, CH),
6.86-7.40 (m, 6H, arom. H).
MS (DCI, isobutane): m/e=299 (M+H.sup.+), 298 (M.sup.+), 257 (M.sup.+
--C.sub.3 H.sub.5).
PROCESS EXAMPLE 21
2-(p-Fluorophenyl)-3,5,6-triisopropyl-1,4-benzoquinone (scheme 3, formula
XX)
60.0 g (201 mmol) of 1-(p-fluorophenyl)-2,4,5-triisopropylbenzene were
introduced into a 2 1 flask containing a mechanical stirrer, efficient
reflux condensers dropping funnel, internal thermometer and inert gas
inlet/bubble counter. A solution of 68 ml of 70% strength aqueous hydrogen
peroxide in 333 ml of trifluoroacetic acid was added dropwise at
-20.degree. C. The cooling bath was removed, but was kept ready for
immediate use again. The reaction mixture warmed to about +20.degree. C.
in the course of 30 min. A very exothermic reaction commenced at this
temperature, control of which required immediate cooling with a dry ice
cooling bath. Despite this cooling, the reaction mixture warmed to reflux.
The cooling was then controlled in such a way that a slight reflux was
maintained. After 10-15 min, the exothermic reaction decreased and TLC
(cyclohexane/toluene 1:1) showed the complete reaction of the starting
material (R.sub.f =0.72) to give the yellow reaction product (R.sub.f
=0.45) and polar byproducts.
The reaction mixture was cautiously poured into ice-cold sodium hydrogen
carbonate solution and extracted 3 times using ether. The combined ether
phases were washed twice with sodium hydrogen carbonate solution, then
with sodium chloride solution, dried and concentrated. The residue was
chromatographed through silica gel using cyclohexane/toluene 2:1 and gave
14.6 g (44.5 mmol, yield 22.1%) of an intensively yellow solid (title
compound), m.p. 122.degree.-124.degree. C.
According to .sup.1 H-NMR and MS, the title compound prepared in this way
contained about 10% of an impurity (MW=344) which could not be separated
by chromatography.
NMR (270 MHz): .delta.=1.15-1.40 (m, 18H, CH.sub.3), 1.98 (sept., 1H, CH),
2.63 (sept., 1H, CH), 3.24 (sept., 1H, CH), 7.08 (AA'BB' system, 4H,
arom. H).
MS (CDI, isobutane): m/e=329 (M+H.sup.+).
PROCESS EXAMPLE 22
2-(p-Fluorophenyl)-3,5,6-triisopropyl-1,4-hydroquinone (scheme 3, formula
III/4)
6.3 g (166.5 mmol) of sodium borohydride were added at room temperature
under nitrogen to a solution of 11.1 g (33.8 mmol) of the quinone from
Process Example 21 in 740 ml of ethanol. After stirring for one hour,
decolorization of the yellow solution occurred. The ethanol was removed in
vacuo and the mixture was aerated with nitrogen (on admission of oxygen
reoxidation of the hydroquinone formed takes place with yellow
coloration). 500 ml of nitrogen-flushed, 2 normal hydrochloric acid were
cautiously added to the residue with ice-cooling (vigorous evolution of
hydrogen, evolution of heat) and the mixture was shaken with 500 ml of
ether which had been decanted from lithium aluminum hydride. The ether
phase was separated off, concentrated in vacuo and aerated with nitrogen.
The residue was dried in a high vacuum, stirred with n-pentane, filtered
off with suction under nitrogen and washed with n-pentane, then dried in a
high vacuum. 9.65 g (29.2 mmol, 86.4% yield) of colorless solid (title
compound) were obtained, m.p. 193.degree.-196.degree. C.
NMR (270 MHz): .delta.=1.23 (d, 6H, CH.sub.3), 1.34 (d, 6H, CH.sub.3), 1.42
(d, 6H, CH.sub.3), 2.66 (sept., 1H, CH), 3.40-3.70 (s, very broad,
probably limited rotation of the isopropyl groups, 2H, CH), 4.12 (s, 1H,
OH), 4.39 (s, 1H, OH), 7.12-7.28 (m, 4H, arom. H).
MS (DCI, isobutane): m/e=330 (M.sup.+).
PROCESS EXAMPLE 23
2,5,6-Triisopropyl-3-(p-fluorophenyl)-4-acetoxyphenol (scheme 3, formula
III/5)
1.73 ml (18.34 mmol, 1.5 equiv.) of acetic anhydride, followed by 23 ml of
degassed, dry pyridine, were added with ice-cooling to 4.04 g (12.23 mmol)
of the hydroquinone from Process Example 22. The reaction mixture was
allowed to stand at 0.degree. C. under argon and with exclusion of
moisture in a refrigerator for 3 days. TLC (cyclohexane/diisopropyl ether
4:1) showed extensive reaction of the starting material (R.sub.f =0.60)
and formation of the title compound (R.sub.f =0.36) as the main product,
in addition to the diacetate (scheme 3, formula XXI) (R.sub.f =0.21) and
the regioisomeric monoacetate (scheme 3, formula III/6) (R.sub.f =0.41) as
by-products. The reaction mixture was poured into 200 ml of 2N
hydrochloric acid and 500 ml of ether and the mixture was shaken. The
ether phase was washed successively with 100 ml of 2N hydrochloric acid
twice, 100 ml of sodium hydrogen carbonate solution and 50 ml of saturated
sodium chloride solution, dried, filtered and concentrated.
The residue (4.10 g) was dissolved in a little toluene with warming, and
this solution was applied to a silica gel column and eluted with
cyclohexane/diisopropyl ether 5:1. After a little starting material (200
mg, 0.61 mmol), initially 150 mg (0.40 mol) of 2.3,5-triiso
propyl-4-acetoxy-6-(p-fluorophenyl)phenol (scheme 3, formula III/6) were
eluted, followed by 2.14 g (5.75 mmol, yield 47.0%) of the title compound,
followed by 940 mg (2.27 mmol) of
1,4-diacetoxy-2,3,5-triisopropyl-6-(p-fluorophenyl)benzene (scheme 3,
formula XXI).
Total yield of all acetylation products, relative to unreacted starting
material, 72.5%.
The title compound was obtained as a colorless solid, m.p.
192.degree.-195.degree. C.
NMR (60 MHz): .delta.=1.15-1.53 (3 xd, 18H, CH.sub.3), 1.72 (s, 3H,
CO--CH.sub.3), 2.3-3.8 (m, 3H, CH), 4.81 (s, 1H, OH), 6.98-7.26
(AA'BB'-system, 4H, arom. H),
MS (DCI, isobutane): m/e=373 (M+H.sup.+) , 372 (M.sup.+), 330 (M+H.sup.+
--CH.sub.3 CO).
PROCESS EXAMPLE 24
1,4-Diacetoxy-2,3,5-triisopropyl-6-(p-fluorophenyl)benzene (scheme 3,
formula XXI)
3.46 ml (36.7 mmol, 3.0 equiv.) of acetic anhydride, followed by 23 ml of
dry pyridine, were added with ice-cooling to 4.04 g (12.23 mmol) of the
hydroquinone from Process Example 22. The reaction was carried out, and
the product was worked up and purified by chromatography as indicated in
Process Example 23. In addition to small amounts of the regioselective
monoacetates, 3.06 g (8.22 mmol, yield 67.2%) of the title compound were
obtained as a colorless solid, m.p. 172.degree.-173.degree. C.
NMR (60 MHz): .delta.=0.9-1.6 (m, 18H, CH.sub.3, hindered rotation), 1.70
(s, 3H, CO--CH.sub.3)1 2.35 (s, 3H, CO--CH.sub.3), 2.43-3.73 (m, 3H, CH),
6.97-7.20 (AA'BB'-system, 4H, arom. H).
MS (DCI, isobutane): m/e=415 (M+H.sup.+), 414 (M.sup.+), 373 (M+H.sup.+
--CH.sub.2 .dbd.C.dbd.O) 372 (M.sup.+ --CH.sub.2 .dbd.C.dbd.O), 331
(M+H.sup.+ --2 CH.sub.2 .dbd.C.dbd.O) 330 (M.sup.+ --2 CH.sub.2
.dbd.C.dbd.O).
PROCESS EXAMPLE 25
2,3,5-Triisopropyl-4-acetoxy-6-(p-fluorophenyl)phenol (scheme 3, formula
III/6)
A solution of 114.2 mg (4.77 mmol, 1.1 equivalents) of lithium hydroxide in
9.83 ml of water was added to a solution of 1.8 g (4.34 mmol) of the
diacetate from Process Example 24 in 30 ml of 1,2-dimethoxyethane. The
reaction mixture was stirred at room temperature. After a short time, a
colorless solid precipitated, and after stirring for 3 days, a clear
solution was obtained. TLC (cf. Process Example 20) showed only traces of
the diacetate, and the title compound as the main product in addition to
the regioisomeric monoacetate as a by-product.
The reaction mixture was poured into 2N hydrochloric acid and extracted
using ether. The extract was washed with sodium hydrogen carbonate
solution and then with saturated sodium chloride solution, dried and
concentrated. Column chromatography (cf. Process Example 23) gave 980 mg
(2.63 mmol, 60.6% yield) of the title compound as a colorless solid, m.p.
174.degree.-177.degree. C. In addition, 480 mg (1.29 mmol, 29.7% yield) of
a compound which was identical to that from Process Example 23 were
obtained.
NMR (60 MHz): .delta.=0.85-1.53 (m, 18H, CH.sub.3), hindered rotation),
2.32 (s, 3H, CO--CH.sub.3), 2.40-3.65 (m, 3H, CH), 4.40 (s, 1H, OH),
7.0-7.36 (m, 4H, arom. H).
PROCESS EXAMPLE 26
tert.-Butyl
(3R,5S)-6-methylsulfonyloxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate
(formula IV)
116.2 g (1.01 mol, 1.5 equiv.) of methanesulfonyl chloride were added
dropwise at 0.degree.-5.degree. C. to a solution of 175.7 g (676 mmol) of
tert.-butyl (3R,5S)-6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate
(see EPA 0,319,847) in 1.7 l of absolute methylene chloride and 1.7 l of
absolute pyridine. The reaction mixture was stirred with ice-cooling for
90 min., and it was then concentrated in vacuo at 30.degree. C. and the
major amount of the residual pyridine was removed by stripping off in
vacuo after taking up in toluene. The residue was taken up in toluene and
the solution was washed twice with water, once with saturated sodium
hydrogen carbonate solution and once with saturated sodium chloride
solution, then dried, filtered and concentrated in vacuo. The oil which
remained crystallized virtually completely at room temperature within a
few minutes. The crystals were filtered off with suction, powdered on the
suction filter, washed with cold petroleum ether and dried in vacuo.
192.0 g (568 mmol) of colorless solid; m.p. 75.degree.-76.degree. C., were
obtained. Concentrating the filtrate, filtering off the crystals with
suction and washing with a little cold petroleum ether yielded a further
34.8 g (103 mmol) of slightly impure product, m.p. 69.degree.-73.degree.
C. Total yield of title compound: 226.8 g (671 mmol, 99.3%).
NMR (270 MHz, CD.sub.2 Cl.sub.2): .delta.=1.18-1.33 (m, 1H, CH.sub.2,
axial), 1.36 (s, 3H, CH.sub.3 ) 1.42 (s, 9H, tert.-Bu), 1.46 (s, 3H,
CH.sub.3 ) 11.56 (dt, 1H, CH.sub.2, equatorial), 2.36 (AB part of ABX
system, 2H, CH.sub.2), 3.03 (s, 3H, CH.sub.3 --SO.sub.2), 4.09-4.23 (m,
3H, OCH.sub.2 and O--CH), 4.24-4.37 (m, 1H, OCH).
MS (DCI, isobutane): m/e=283 (M+H.sup.+ ->=).
PROCESS EXAMPLE 27
(2,2-Dimethyl-4(S)-[(2-p-fluorophenyl-4-p-fluorophenylthio-6-isopropyl)phen
oxymethyl]-6(R)-tert.-butoxycarbonylmethyl}-1,3-dioxolane (formula V)
2.02 g (14.6 mmol, 1.3 equiv.) of powdered potassium carbonate and about 10
mg of crown ether 18-crown-6 (Aldrich) were added to a solution of 4.0 g
(11.2 mmol) of 2-(p-fluorophenyl)-4-p-fluorophenylthio)-6-isopropylphenol
(Process Example 6) in 25 ml of dry hexamethylphosphoramide (HMPT). The
suspension was stirred at room temperature for 20 min, then 4.55 g (13.5
mmol, 1.2 equiv.) of tert.-butyl
(3R,5S)-6-methylsulfonyloxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate
(Process Example 26) were added and the mixture was stirred at
75.degree.-80.degree. C. for 2 days. The reaction mixture became
dark-colored and more viscous. It was poured into 200 ml of aqueous sodium
dihydrogen phosphate solution and extracted several times using ether. The
combined extracts were washed with saturated sodium chloride solution,
dried and concentrated in vacuo and gave 8.64 g of a brownish oil.
Column chromatography (cyclohexane/ethyl acetate 10:1 plus 1 part per
thousand of triethylamine) gave 4.96 g (8.28 mmol, 74.0% yield) of a pale
yellow, viscous oil (title compound).
NMR (270 MHz, C.sub.6 D.sub.6): .delta.=0.98-1.07 (m, 2H, CH.sub.2),
1.19+1.20 (2 xd, 6H, CH(CH.sub.3).sub.2), 1.38 (s, 9H, tert.-Bu),
1.39+1.41 (2xs, 6H, OC(CH.sub.3).sub.2), 2.12 (dd, 1H, CH.sub.2 CO.sub.2),
2.42 (dd, 1H, CH.sub.2 CO.sub.2), 3.27 (dd, 1H, O-CH.sub.2), 3.37 (dd, 1H,
O--CH.sub.2) 3.65 (sept., 1H, CH(CH.sub.3).sub.2), 3.65-3.76 (m, 1H,
O--CH), 4.10-4.21 (m, 1H, O--CH), 6.60+6.82 (AA'BB' system, 4H, arom. H),
7.12-7.18 (m, 2H, arom. H), 7.22-7.29 (m, 3H, arom. H), 7.45 (d, 1H, arom.
H).
MS (DCI, isobutane): m/e=598 (M.sup.+), 543 (M+H.sup.+ ->=), 485.
PROCESS EXAMPLE 28
tert.-Butyl
3(R),5(S)-dihydroxy-6-[(2-p-fluorophenyl-4-p-fluorophenylthio-6-isopropyl)
phenoxy]hexanoate (formula II/1)
A solution of 4.47 g (7.47 mmol) of the acetonide from Process Example 27
in 50 ml of tetrahydrofuran, 50 ml of ethanol and 5 ml of 2N hydrochloric
acid was stirred at room temperature for 16 hours. TLC (cyclohexane/ethyl
acetate 1:1) showed nearly quantitative conversion of the starting
material (R.sub.f =0.78) to the product (R.sub.f =0.59). The reaction
mixture was poured into aqueous sodium hydrogen carbonate solution and
extracted several times using ether. The extracts were washed with
saturated sodium chloride solution, dried and concentrated in vacuo. The
residue (4.46 g of brownish oil) was purified by column chromatography
(cyclohexane/ethyl acetate 2:1) and gave 3.37 g (6.03 mmol) of title
compound as a colorless oil (yield 80.8%).
NMR (270 MHz, C.sub.6 D.sub.6): .delta.=1.1-about 1.4 (m, partially covered
by strong singlets, 2H, CH.sub.2) 1.18 (d, 6H, CH(CH.sub.3).sub.2), 1.31
(s, 9H, tert.-Bu), 2.00 (dd, 1H, CH.sub.2 --CO.sub.2) 2.13 (dd, 1H,
CH.sub.2 --CO.sub.2), 3.15 (s,, broad, 1H, OH), 3.36 (AB part of ABX
systems, 2H, OCH.sub.2), 3.52 (s, broad, 1H, OH), 3.56 (sept., 1H,
CH(CH.sub.3).sub.2), 3.76-3.96 (m, 2H, 2 x CHOH), 6.61+6.79 (AA'BB'
system, 4H, arom. H), 7.14-7.27 (m, 5H, arom. H), 7.45 (d, 1H, arom. H).
MS (FAB, 3-NBA): m/e=558 (M.sup.+), 519, 503 (M.sup.+ ->=+H.sup.+), 356
(M.sup.+ of the phenol building block).
PROCESS EXAMPLE 29
{2,2-Dimethyl-4(S)-[(2-p-fluorophenyl-4-p-fluorophenylthio-6-cyclopropyl)ph
enoxymethyl]-6(R)-tert.-butoxycarbonylmethyl}-1,3-dioxolane (formula V)
In analogy to Process Example 27, 2.44 g (4.09 mmol, 73.0% yield) of the
title compound were obtained as a pale yellow, viscous oil from 2.0 g (5.6
mmol) of 2-(p-fluorophenyl)-4-(p-fluorophenylthio)-6-cyclopropylphenol
(Process Example 12).
NMR (270 MHz, C.sub.6 D.sub.6): .delta.=0.78 (m, 4H, CH.sub.2), 1.98-1.07
(m, 2H,, CH.sub.2)1 1.38 (8, 9H, tert.-Bu), 1.39+1.41 (2 xs, 6H,
OC(CH.sub.3)2), 1.87 (qui, 1H, CH), 2.13 (dd, 1H, CH.sub.2 CO.sub.2), 2.42
(dd, 1H, CH.sub.2 CO.sub.2), 3.32 (AB part of ABX system, 2H, OCH.sub.2)
3.64-3.77 (m, 1H, O--CH), 4.10-4.22 (m, 1H, O--CH), 6.61+6.83
(AA'BB'system, 4H, arom. H), 7.10-7.30 (m, 5H, arom. H), 7.46 (d, 1H,
arom. H).
MS (DCI, isobutane): m/e=596 (M.sup.+), 541 (M+H.sup.+ ->=).
PROCESS EXAMPLE 30
tert.-Butyl
3(R),S(S)-dihydroxy-6-[(2-p-fluorophenyl-4-p-fluorophenylthio-6-cyclopropy
l)phenoxy]hexanoate (formula II/1)
In analogy to Process Example 28, 1.64 g (2.95 mmol, 72. 1% yield) of the
title compound were obtained as a colorless, viscous oil from 2.44 g (4.09
mmol) of the acetonide from Process Example 29.
NMR (270 MHz, C.sub.6 D.sub.6) 0.77 (m, 4H, CH.sub.2) 1.10-1.35 (m,
partially covered, 2H, CH.sub.2) 1 1.31 (s, 9H, tert.-Bu), 1.87 (qui, 1H,
CH), 1.95-2.18 (AB part of ABX system, 2H, CH.sub.2 CO.sub.2 --), 3.15 (s,
broad, 1H, OH), 3.37 (AB part of ABX system, 2H, OCH.sub.2), 3.53 (s,
broad, 1H, OH), 3,75-3.97 (m, 2H, CHOH), 6.61+6.80 (AA'BB' system, 4H,
arom. H), 7.13-7.28 (m, 5H, arom. H), 7.45 (d, 1H, arom. H).
MS (FAB, 3-NBA): m/e=556 (M.sup.+) , 354 (M.sup.+ of the phenol building
block).
PROCESS EXAMPLE 31
{2,2-Dimethyl-4(S)-[[2-(p-fluoro-a-methylphenyl)-4-p-fluorophenylthio-6-iso
propyl]phenoxymethyl]-6(R)-tert.-butoxycarbonylmethyl}-1,3-dioxolane
(formula V)
In analogy to Process Example 27, 5.15 g (8.41 mmol, 74.1% yield) of the
pure title compound were obtained as a colorless, viscous oil from 4.2 g
(11.35 mmol) of
2-(p-fluoro-m-methylphenyl)-4-(p-fluorophenylthio)-6-isopropylphenol
(Process Example 15) and 4.55 g (13.5 mmol) of the mesylate (Process
Example 26) after chromatography.
NMR (270 MHz, C.sub.6 D.sub.6): .delta.=0.97-1.09 (m, 2H, CH.sub.2), 1.20
(d, finely split, 6H, CH(CH.sub.3).sub.2), 1.38 (s, 9H, tert.-Bu),
1.39-1.41 (2 xs, 6H, OC(CH.sub.3).sub.2), 2.13 (dd, 1H, CH.sub.2
CO.sub.2), 2.35 (s, 3H, CH.sub.3), 2.43 (dd, 1H, CH.sub.2 CO.sub.2), 3.28
(dd, 1H, O--CH.sub.2), 3.38 (dd, 1H, O-CH.sub.2) 3.65 (sept., 1H,
CH(CH.sub.3).sub.2), 3.65-3.76 (m, 1H, O--CH), 4.09-4.22 (m, 1H, O--CH),
6.60-7.44 (m, 9H, arom. H).
MS (DCI, isobutane): m/e=612 (M.sup.+), 557 (M+H.sup.+ ->=).
PROCESS EXAMPLE 32
tert.-Butyl
3(R),5(S)-dihydroxy-6-[(2-p-fluoro-m-methylphenyl-4-p-fluorophenylthio-6-i
sopropyl)phenoxy]hexanoate (formula II/1)
In analogy to Process Example 28, 3.70 g (6.47 mmol, yield 77.7%) of
colorless oil were obtained from 5.10 g (8.33 mmol) of the acetonide from
Process Example 31 after chromatography.
MS (FAB, 3-NBA): m/e=572 (M.sup.+), 517 (M.sup.+ ->=+H.sup.+), 370 (M.sup.+
of the phenol building block).
PROCESS EXAMPLE 33
{2,2-Dimethyl-4(S)-[(2-p-fluorophenyl-4-phenylthio-6-isopropylphenoxymethyl
]-6 (R) -tert. -butoxycarbonylmethyl}-1,3-dioxolane (formula V)
In analogy to Process Example 27, 5.4 g (9.31 mmol, 67.0% yield) of a
colorless, viscous oil were obtained from 4.7 g (13.90 mmol) of
2-p-fluorophenyl-4-phenylthio-6-isopropylphenol (Process Example 7) after
chromatography.
NMR (270 MHz, C.sub.6 D.sub.6): .delta.=0.97-1.08 (m, 2H, CH.sub.2), 1.20
(2 xd, 6H, CH(CH.sub.3).sub.2), 1.37 (s, 9H, tert.-Bu), 1.39+1.41 (2 xs,
6H, OC(CH.sub.3)2), 2.13 (dd, 1H, CH.sub.2 CO.sub.2), 2.42 (dd, 1H,
CH.sub.2 CO.sub.2), 3.32 (AB part of ABX system, 2H, OCH.sub.2) 3.66
(sept., 1H, CH(CH.sub.3) 2), .about.3.65-3.77 (m, 1H, O--CH), 4.09-4.22
(m, 1H, O--CH), 6.62-7.28 (m, 11H, arom. H).
MS (DCI, isobutane): m/e=580 (M.sup.+), 525 (M+H.sup.+ ->=), 467.
PROCESS EXAMPLE 34
tert.-Butyl 3(R),5(S)-dihydroxy-6-[(2-p-fluorophenyl-4-
phenylthio-6-isopropyl)-phenoxy]hexanoate (formula II/1)
In analogy to Process Example 28, 3.65 g (6.76 mmol, yield 73.3%) of
colorless, viscous oil were obtained from 5.35 g (9.2 mmol) of the
acetonide from Process Example after chromatography.
MS (FAB, 3-NEA): m/e=540 (M.sup.+), 501, 485 (M.sup.+ ->=+H.sup.+), 338
(M.sup.+ of the phenol building block).
PROCESS EXAMPLE 35
(2,2-Dimethyl-4(S)-[(2-p-fluorophenyl-4-isopropylthio-6-isopropylphenoxymet
hyl]-6(R)-tert.-butoxycarbonylmethyl}-1,3-dioxolane (formula V)
A suspension of 206 mg (0.68 mmol) of
2-(p-fluorophenyl)-4-(isopropylthio)-6-isopropylphenol (Process Example
8), 271 mg (0.80 mmol) of tert.-butyl
(3R,5S)-6-methylsulfonyloxy-3,5-O-isopropylidene-3.5-dihydroxyhexanoate
(Process Example 26), 221 mg (1.60 mmol) of powdered potassium carbonate
and a microspatula tip full (1-2 mg) of crown ether 18-crown-6 in 6.8 ml
of dry hexamethylphosphoramide was heated at 65.degree.-70.degree. C. for
12 hours, then at 80.degree. C. for a further 6 hours. TLC
(cyclohexane/ethyl acetate 5:1) showed complete conversion of the starting
phenol. The reaction mixture was cooled, poured into sodium hydrogen
carbonate solution and extracted twice using ether. The combined ether
phases were washed twice with water and once with saturated sodium
chloride solution, dried, filtered and concentrated. The residue was
chromatographed on silica gel using toluene/ethyl acetate 30:1, later
20:1, and gave:
in fractions 6-8 40.1 mg of an unidentified reaction product, R.sub.f
(toluene/ethyl acetate, 20:1):0.40,
in fractions 10-15 110.3 mg of the title compound, R.sub.f : 0.32, pale
yellow, viscous oil,
in fractions 23-27 32.5 mg of a compound which, on the basis of .sup.1
H-NMR and MS, is allocated the structure
##STR28##
R.sub.f : 0.14, pale yellow, viscous oil,
in fractions 30-35 40.7 mg of a compound which, on the basis of .sup.1
H-NMR and MS, is allocated the structure
##STR29##
R.sub.f : 0.08, pale yellow, viscous oil. Spectra of the title compound
(fractions 10-15):
NMR (270 MHz): .delta.=0.97 (d, 6H, SC(CH.sub.3).sub.2), 1.22 (d, finely
split, 6H, CH(CH.sub.3).sub.2), 1.15-1.33 (m, 1H, CH.sub.2), 1.38 (s, 3H,
CH.sub.3), 1.42 (s, 3H, CH.sub.3), 1.45 (s, 9H, tert.-Bu), 1.82 (dt, 1H,
CH.sub.2), 2.37 (AB part of ABX system, 2H, CH.sub.2), 2.87 (dd, 1H,
OCH.sub.2), 3.09 (dd, 1H, OCH.sub.2), 3.45 (sept., 1H, CH), 3.64 (sept.,
1H, CH), 4.02 (m, 1H, CH), 4.23 (m, 1H, CH), 7.03-7.53 (m, 6H, arom. H).
MS (DCI, isobutane): m/e=546 (M.sup.+), 489 (M.sup.+ tert.-Bu), 433.
Spectra of fractions 23-27:
NMR (270 MHz): .delta.=1.06 (AB system, 4H, CH.sub.2), 1.20+1.21 (2 xd,
12H, CH(CCH.sub.3).sub.2), 1.32 (s, 6H, C(CH.sub.3).sub.2), 1.40 (s, 6H,
C(CH.sub.3).sub.2), 1.43 (s, 18H, tert.-Bu), 2.33 (AB part of ABX system,
4H, CH.sub.2 CO.sub.2), 3.20-3.51 (m, 6H, OCH.sub.2 and CH(CH.sub.3)2),
3.89 (m, 2H, CH), 4.19 (m, 2H, CH), 7.00-7.51 (m, 12H, arom. H).
MS (FAB): m/e=1006 (M.sup.+), 223.
Spectra of fractions 30-35:
NMR (270 MHz): .delta.=1.07 (.about.qua, 1H, CH.sub.2), 1.16-.about.1.30
(covered, 2H, CH.sub.2), 1.24 (2 xd, 6H, CH(CH.sub.3).sub.2), 1.32 (s, 3H,
CH.sub.3), 1.37 (s, 3H, CH.sub.3), 1.39 (s, 3H, CH.sub.3), 1.41 (s, 3H,
CH.sub.3), 1.43+1.44 (2 xs, 18H, tert. -Bu) 1.80 (dt, 1H, CH.sub.2),
2.21-2.48 (2xAB part of ABX system, 4H, CH.sub.2 CO.sub.2), 2.87 (dd, 1H,
SCH.sub.2), 3.08 (dd, 1H, SCH.sub.2), 3.26 (dd, 1H, OCH.sub.2), 3.37 (dd,
1H, OCH.sub.2)1 3.47 (sept., 1H, CH(CH.sub.3).sub.2), 3.89 (m, 1H, CH),
4.02 (m, 1H, CH), 4.22 (m, 2H, CH), 7.03-7.26 (m, 4H, arom. H), 7.45-7.52
(m, 2H, arom. H).
MS (DCI, isobutane): m/e=748 (M.sup.+), 689 (M.sup.+ -tert.-BU) 577, 519.
PROCESS EXAMPLE 36
tert.-Butyl
3(R),5(S)-dihydroxy-6-[2-p-fluorophenyl-4-isopropylthio-6-isopropyl)phenox
y]hexanoate (formula II/1)
In analogy to Process Example 28, 74 mg of colorless, viscous oil were
obtained from 100 mg of the acetonide (Process Example 35, fractions
10-15) after chromatography.
MS (FAB, 3-NBA): m/e=506 (M.sup.+) , 451 (M.sup.+ ->=+H.sup.+) , 304
(M.sup.+ of the phenol building block).
PROCESS EXAMPLE 37
<2,2-Dimethyl-4(S)-{2-isopropyl-4-[(3-isopropyl-4-hydroxy-5-p-fluorophenyl-
l-phenylthio)-2-propyl-2-thio]-6-p-fluorophenylphenoxymethyl)-6(R)-tert.-bu
toxycarbonylmethyl>-1,3-dioxolane (scheme 2, formula V/1)
##STR30##
and
4,4-(Isopropylidenedithio)-bis-<{1-[(2S,4R)-2,4-O-isopropylidene-
2,4-dihydroxy-5tert.-butoxycarbonyl]pentoxy-2-isopropyl-6-p-fluorophenyl}b
enzene> (scheme 2, formula XII)
##STR31##
Batch 1: Preferred formation of the monocoupling product
A suspension of 4.30 g (7.61 mmol) of
4,4-(isopropylidenedithio)-bis-[-2-isopropyl-6-p-fluorophenyl)phenol](Proc
ess Example 5), 2.50 g (18.09 mmol) of powdered potassium carbonate and 10
mg of crown ether 18-crown-6 in 50 ml of dry HMPT was stirred at room
temperature for 30 min. 3.09 g (9.13 mmol, 1.2 equivalents) of tert.-butyl
(3R,5S)-6-methylsulfonyloxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate
(Process Example 26) were added and the reaction mixture was stirred at
80.degree.-85.degree. C. for 12 hours. The cooled reaction mixture was
poured into 25% strength aqueous sodium dihydrogen phosphate solution and
extracted twice using ether. The extracts were washed with saturated
sodium chloride solution, dried and concentrated. The residue showed two
products (R.sub.f =0.34 and 0.26) on TLC analysis
(cyclohexane/toluene/ethyl acetate/triethylamine 10:10:1:10.sup.-3) in
addition to a trace of the starting phenol (R.sub.f =0.49). Column
chromatography on silica gel using this eluent gave 2.598 g (3.22 mmol) of
the less polar monocoupling product, yield 42.3%, as a colorless solid,
m.p. 47.degree.-50.degree. C. and 1.704 g (1.62 mmol) of the polar double
coupling product, yield 21.3%, as a colorless solid, m.p.
48.degree.-51.degree. C.
Spectra of the monocoupling product:
NMR (270 MHz, C.sub.6 D.sub.6): 6 0.98-1.07 (m, 2H, CH.sub.2)
1.24/1.28/1.30 (3 xs, 12H, CH(CH.sub.3).sub.2), 1.38 (s, 9H, tert.-Bu),
1.38/1.39 (2 xs, 6H, OC(CH.sub.3).sub.2), 1.67 (s, 6H,
S--C(CH.sub.3).sub.2), 2.12 (dd, 1H, CH.sub.2 CO.sub.2), 2.42 (dd, 1H,
CH.sub.2 CO.sub.2), 3.22-3.42 (m, 3H, OCH.sub.2 +CH(CH.sub.3).sub.2),
3.62-3.68 (m, 2H, CH+CH(CH.sub.3).sub.2), 4.10-4.22 (m, 1H, CH) ,
6.62-7.15 (m, 6H, arom. H), 7.32-7.41 (m, 2H, arom. H),
7.51/7.67/7.78/7.87 (4 xd, 4 x1H, arom. H).
MS (FAB, 3-NEA/LiI): m/e=813 (M+Li.sup.+) , 625, 303.
Spectra of the double coupling product:
NMR (270 MHz, C.sub.6 D.sub.6): .delta.=0.90-1.08 (m, 4H, CH.sub.2), 1.28
and 1.32 (d, 12H, CH(CH.sub.3).sub.2), 1.39 (s, 18H, tert.-Bu), 1.40 (2
xs, 12H, OC(CH.sub.3).sub.2), 1.66 (s, 6H, S--C(CH.sub.3)2--S), 2.12 (dd,
2H, CH.sub.2 CO.sub.2), 2.43 (dd, 2H, CH.sub.2 CO.sub.2), 3.27 (dd, 2H,
OCH.sub.2), 3.39 (dd, 2H, OCH.sub.2), 3.63-3.78 (m, 4H, CH(CH.sub.3)2 and
CH), 4.11-4.23 (m, 2H, CH), 6.82-6.91 (m, 4H, arom. H), 7.32-7.42 (m, 4H,
arom. H), 7.68 (d, 2H, arom. H), 7.88 (d, 2H, arom. H).
MS (FAB, 3-NBA/LiI): m/e=1055 (M+Li.sup.+) , 746, 625, 431, 303.
Batch 2: Preferred formation of the double coupling product
A suspension of 26.0 g (46 mmol) of the phenol (Process Example 5), 15.3 g
(110.4 mmol, 1.4 equivalents) of potassium carbonate and 50 mg of
18-crown-6 in 150 ml of dry HMPT were stirred at room temperature for 15
min. 23.3 g (69 mmol, 1.5 equivalents) of the mesylate (Process Example
26) were added and the reaction mixture was stirred at 85.degree. C. for
15 hours. The viscous reaction mixture was diluted with a further 100 ml
of HMPT and heated to 85.degree. C. for a further 4 hours. The cooled
reaction mixture was poured into 2N hydrochloric acid/ice (1:1), extracted
using ether, and the extracts were washed with sodium chloride solution,
dried and concentrated. Column chromatography (cyclohexane/toluene/ethyl
acetate 30:10:1.fwdarw.10:10:1) gave 11.84 g (31.9% yield) of the
monocoupling product and 19.80 g (41.0% yield) of the double coupling
product.
PROCESS EXAMPLE 38
tert.-Butyl
3(R),5(S)-Dihydroxy-6-{2-isopropyl-4-[(3-isopropyl-4-hydroxy-5-p-fluorophe
nyl-l-phenylthio)-2-propyl-2-thiol-6-p-fluorophenylphenoxyyhexanoate
(formula II/1)
A solution of 11-84 g (14.7 mmol) of the monocoupling product (Process
Example 37, batch 2) in 50 ml of THF, ml of ethanol and 10 ml of 2N
hydrochloric acid was stirred at room temperature for 16 hours. The
reaction mixture was poured into sodium hydrogen carbonate solution, the
mixture was extracted three times with ether and the extracts were washed
with sodium chloride solution, dried and concentrated. The residue was
chromatographed on silica gel using toluene/ethyl acetate
(20:1.fwdarw.5:1) and gave 7.8 g (10.17 mmol, 69.3% yield) of a colorless,
viscous Oil.
NMR (270 MHz, C.sub.6 D.sub.6): .delta.=1.08-1.22 (m, 2H, CH.sub.2),
1.26/1.27 (2 xd, 12H, CH(CH.sub.3).sub.2), 1.32 (s, 9H, tert.-Bu), 1.67
(s, 6H, S--C(CH.sub.3)2--S), 2.00 (dd, 1H, CH.sub.2 CO.sub.2), 2.14 (dd,
1H, CH.sub.2 CO.sub.2), 3.08 (d, 1H, OH), 3.28-3.42 (m, 3H, OCH.sub.2 and
CH(CH.sub.3).sub.2), 3.51 (d, 1H, OH), 3.59 (sept., 1H,
CH(CH.sub.3).sub.2), 3.77-3.96 (m, 2H, CH), 4.97 (s, 1H, OH), 6.63-6.98
(m, 6H, arom. H) s, 7.32 (m, 2H, arom. H), 7.51/7.67/7.78/7.87 (4 xd, 4
x1H, arom. H).
MS (FAB, 3-NBA/LiI): m/e=773 (M+Li.sup.+), 415, 303.
PROCESS EXAMPLE 39
4,4-(Isopropylidenedithio)-bis-<{1-[(2S,4R)@hydroxy-5-tert.-butoxycarbonyl]
pentoxy-2-isopropyl-6-p-fluorophenyl}benzene>
A solution of 12.2 g (11.3 mmol) of the double coupling product (Process
Example 37, batch 2) in 250 ml of THF, 250 ml of ethanol and 20 ml of 2N
hydrochloric acid was stirred at room temperature for 12 hours. The
reaction mixture was poured into aqueous sodium dihydrogen phosphate
solution, the mixture was extracted three times using ether and the
extracts were washed with sodium chloride solution, dried and
concentrated. Column chromatography (silica gel) of the residue using
toluene/ethyl acetate 6:1 gave 798 mg (6.8% yield) of a colorless oil, in
which only one of the two acetonide groups was hydrolyzed and which had
the following formula:
##STR32##
MS (FAB, 3-NEA/LiI): m/e=1015 (M+Li.sup.+), 449, 303.
Further elution using methylene chloride/methanol 10:1 gave 8.67 g (77%
yield) of the title compound as a viscous oil.
NMR (270 MHz, C.sub.6 D.sub.6): .delta.=1.12-1.23 (m, 2H, CH.sub.2), 1.28
(d, 12H, CH(CH.sub.3).sub.2), 1.32 (s, 18H, tert.-Bu), .about.1.35-1.42
(m, 2H, CH.sub.2), 1.66 (s, 6H, S--C(CH.sub.3).sub.2 --S), 2.01 (dd, 2H,
CH.sub.2 CO.sub.2), 2.14 (dd, 2H, CH.sub.2 CO.sub.2), 3.13 (d, 2H, OH),
3.36 (AB part of ABX system, 4H, OCH.sub.2), 3.53 (d, 2H, OH), 3.60 (2H,
sept., CH(CH.sub.3).sub.2), 3.78-3.96 (4H, m, CH), 6.82 (m, 4H, arom. H),
7.32 (m, 4H, arom. H) , 7. 5 6 (d, 2H, arom. H) , 7.87 (d, 2H, arom. H).
MS (FAB, 3-NEA/LiI): m/e=975 (M+Li.sup.+), 455, 449, 415.
PROCESS EXAMPLE 40
{2,2-Dimethyl-4(S)-[(2,3,5-triisopropyl-4-acetoxy-6-p-fluorophenyl)phenoxym
ethyl)-6(R)-tert.-butoxycarbonylmethyl}-1,3-dioxolane (formula V)
A suspension of 650 mg (1.75 mmol) of
2,3,5-triisopropyl-4-acetoxy-6-p-fluorophenylphenol (Process Example 25),
mg (1.90 mmol) of tert.-butyl
(3R,5S)-6-methylsulfonyloxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate
(Process Example 26), 518 mg (3.75 mmol) of potassium carbonate powder and
a crystal of 18-crown-6 in 9.6 ml of absolute DMSO were stirred at
70.degree. C. for 12 hours. The suspension became viscous. A further 9.6
ml of DMSO were added and the temperature was increased to
75.degree.-80.degree. C. After 30 min, a further 320 mg (0.95 mmol) of the
mesylate and 240 mg (1.75 mmol) of potassium carbonate powder were added.
After 10 hours, the reaction mixture was allowed to cool and was poured
into aqueous sodium hydrogen carbonate solution, and the mixture was
extracted three times using ether. The combined ether phases were washed
with sodium hydrogen carbonate solution, then with water and then with
NaCl solution, dried, filtered and concentrated. The residue was
chromatographed through silica gel 35-70 pm using cyclohexane/ethyl
acetate 10:1 +I part per thousand of triethylamine. 770 mg (1.25 mmol,
71.4% yield) of a colorless solid (title compound), m.p.
145.degree.-147.degree. C., were obtained.
NMR (270 MHz, C.sub.6 D.sub.6) : .delta.=[1.08 (m), 1.22 (d), 1.27 (s),
1.32 (d), 1.41 (s), 1.47 (d), altogether 35H, 3 xCH(CH.sub.3).sub.2),
CH.sub.2, O--C(CH.sub.3).sub.2 --O, tert.-Bu, obviously hindered rotation
of the isopropyl groups], 1.94 (s, 3H, OAc), 2.17 (dd, 1H, CH.sub.2
CO.sub.2), 2.48 (dd, 1H, CH.sub.2 CO.sub.2), 3.01 (sept., 1H,
CH(CH.sub.3).sub.2), 3.2-4.0 (m, 5H, OCH.sub.2, CH, 2 xCH(CH.sub.3).sub.2,
signals of the isopropyl groups very broad, obviously hindered rotation),
4.16 (m, 1H, CH), 6.71-7.28 (m, 4H, arom. H).
MS (DCI, isobutane): m/e=614 (M.sup.+), 599 (M.sup.+ --CH.sub.3), 572
(M.sup.+ --CH.sub.2 .dbd.C.dbd.O) 1 559, 557, (M.sup.+ -tert.-Bu), 501.
PROCESS EXAMPLE 41
tert.-Butyl
3(R),5(S)-dihydroxy-6-[(2,3,5-triisopropyl-4-acetoxy-6-p-fluorophenyl)phen
oxy]hexanoate (formula II/1)
A solution of 765 mg (1.15 mmol) of the acetonide (Process Example 40) in
13 ml of ethanol, 13 ml of THF and 1. 3 ml of 2N hydrochloric acid was
stirred at room temperature for 18 hours. TLC (cyclohexane/ethyl acetate
2:1) showed clean, virtually quantitative reaction of the acetonide
(R.sub.f =0.63) to give the product (R.sub.f =0.26). The reaction mixture
was neutralized with potassium hydrogen carbonate powder, ether and water
were added and, after vigorously shaking, the ether phase was separated
off. It was washed with sodium chloride solution, dried, f altered and
concentrated. The residue was chromatographed on silica gel using
cyclohexane/ethyl acetate 2:1+1 part per thousand of triethylamine and
gave 632 mg (1.10 mmol, 95.6% yield) of colorless solid (title compound),
melting point 119.degree.-122.degree. C.
NMR (270 MHz, C.sub.6 D.sub.6) : .delta.=0.9-1.5 (m, 29H, 3
xCH(CH.sub.3).sub.2, tert.-Bu, CH.sub.2 ; obviously hindered rotation of
the isopropyl groups), 1.93 (s, 3H, OAc), 2.12 (AB part of ABX system, 2H,
CH.sub.2 CO.sub.2, [2.99 (m, 2H) and 3.38-4.12 (m, 7H), 3 xCH(CH.sub.3)21
OCH.sub.2, 2 xCH, 2 xOH, obviously hindered rotation of the isopropyl
groups], 6.78 (m, 2H, arom. H), 7.03 (m, 2H, arom. H).
MS (DCI, isobutane) m/e=575 (M+H.sup.+), 574 (M.sup.+), 519 (M+H.sup.+
->=), 330 (M.sup.+ of the hydroquinone building block).
PROCESS EXAMPLE 42
(2,2-Dimethyl-4(S)-[2,5,6-triisopropyl-3-p-fluorophenyl-4-acetoxyphenoxymet
hyl]-6(R)-tert.-butoxycarbonylmethyl}-1,3-dioxolane (formula V)
A suspension of 1.28 g (3.4 mmol) of
2,5,6-triisopropyl-3-p-fluorophenyl-4-acetoxy)phenol (Process Example 23),
1.28 g (3.8 mmol) of tert.-butyl
(3R,5S)-6-methylsulfonyloxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate
(Process Example 26), 1.02 g (7.6 mmol) of potassium carbonate powder and
a crystal of 18-crown-6 in 19 ml of absolute DMSO were stirred at
70.degree. C. for 12 hours, then the temperature was increased to
75.degree.-80.degree. C. After 30 min, a further 575 mg (1.7 mmol) of the
mesylate and 470 mg (3.4 mmol) of potassium carbonate powder were added.
After 10 hours, the mixture was allowed to cool.
Working up and chromatography were carried out as in Process Example 40.
1.23 g (2.0 mmol, yield 60%) of colorless solid (title compound), melting
point 151.degree.-153.degree. C., were obtained.
NMR (270 MHz, C.sub.6 D.sub.6): .delta.=1.04-1.55 [m, 38H, 3
xCH(CH.sub.3).sub.2, O--C(CH.sub.3).sub.2 --O, tert.-Bu, CH.sub.2, OAc,
obviously hindered rotation of the isopropyl groups], 2.22 (dd, 1H,
CH.sub.2 CO.sub.2), 2.51 (dd, 1H, CH.sub.2 CO.sub.2), 3.39 (m, broad 1H,
CH(CH.sub.3).sub.2), 3.58 (sept., 1H, CH(CH.sub.3).sub.2), 3.71 (AB part
of ABX system, 2H, 4.08-4.37 (m, 3H, CH, CH(CH.sub.3).sub.2), 6.71-7.42
(m, 4H, arom. H).
MS (DCI, isobutane): m/e=614 (M.sup.+), 572; 559, 501.
PROCESS EXAMPLE 43
tert.-Butyl
3(R),5(S)-dihydroxy-6-1(2,5,6-triisopropyl-3-p-fluorophenyl-4-acetoxy)phen
oxy]hexanoate (formula II/1)
A solution of 1.22 g (2.0 mmol) of the acetonide (Process Example 42) in 25
ml of ethanol, 25 ml of THF and 2.5 ml of 2N hydrochloric acid was stirred
at room temperature for 18 hours. Working up and chromatography as in
Process Example 41 gave 1.03 g (1.8 mmol, yield 90%) of the title compound
as a colorless solid, melting point 61.degree.-63.degree. C. According to
.sup.1 H-NMR,, this product contained about 5% of an
NMR: At 27.degree. C. (C.sub.6 D.sub.6), most of the signals were broad and
complex. In the same solvent at 70.degree. C., the signals were defined:
.delta.=1.17 (2 xd, 6H, CH(CH.sub.3).sub.2), 1.37 (s, 9H, tert.-Bu),
1.42-1.47 (2 xd+1 xs, 15H, 2 xCH(CH.sub.3).sub.2 +OAc), 1.69 (Ab system,
2H, CH.sub.2), 2.25 (AB part of ABX system, 2H, CH.sub.2 CO.sub.2), 3.03
(s, 1H, OH), 3.31 (s, 1H, OH), 3.35 (sept., 1H, CH(CH.sub.3).sub.2), 3.56
(sept., 1H, CH(CH.sub.3).sub.2), 3.77 (AB part of ABX system, 2H,
OCH.sub.2), 4.02 (sept., 1H, CH(CH.sub.3).sub.2), 4.17 (.about.qui, 1H,
CH), 4.28 (.about.qui, 1H, CH), 6.83 (m, 2H, arom. H), 6.98-7.17 (m, 2H,
arom. H).
MS (DCI, isobutane): m/ep=575 (M+H.sup.+), 574 (M.sup.+), 519 (M+H.sup.+
->=), 330 (M.sup.+ of the hydroquinone building block).
EXAMPLE 1
Sodium
3(R),5(S)-dihydroxy-6-[2-p-fluorophenyl-4-p-fluorophenylthio-6-isopropyl)p
henoxy]hexanoate (formula II/2)
A suspension of 3.07 g (5.50 mmol) of the tert.-butyl ester (Process
Example 28) in 30 ml of ethanol and 5.56 ml (5.56 mmol, 1.01 equivalents)
of 1N sodium hydroxide solution was stirred at room temperature for 3
hours. A clear solution was formed during the course of this and TLC
(chloroform/methanol 4:1) showed complete reaction of the tert.-butyl
ester (R.sub.f =0.82) to give the polar product (R.sub.f =0.62). The
solvents were removed in vacuo. Toluene was twice added to the residue and
in each case stripped off in vacuo in order to remove water residues
azeotropically. The crystalline residue was washed with cyclohexane, then
dried to constant weight in a high vacuum.
2.67 g (93% yield) of a weakly yellow solid (title compound), which melts
at 192.degree.-195.degree. C. with decomposition (dark brown coloration),
were obtained.
NMR (270 MHz, DMSO-d.sub.6): .delta.=1.18 (d, 6H, CH(CH.sub.3).sub.2), 1.29
(t, 2H, CH.sub.2), 1.40 (s, 1H, OH), 1.77 (dd, 1H, CH.sub.2 CO.sub.2),
1.99 (dd, 1H, CH.sub.2 CO.sub.2), 3.21 (AB part of ABX system, 2H,
OCH.sub.2)1 3.46 (sept., 1H, CH(CH.sub.3).sub.2), 3.66 (m, 2H, CH), 4.88
(s, br., 1H, OH), 7.04 (d, 1H, arom. H), 7.18-7.28 (m, SH, arom. H),
7.37-7.57 (m, 4H, arom. H).
EXAMPLE 2
Sodium
3(R),5(S)-dihydroxy-6-[2-p-fluorophenyl-4-p-fluorophenylthio-6-cyclopropyl
)phenoxy]hexanoate (formula II/2)
In analogy to Example 1, 1.25 g of a solid (title compound) which melts at
190.degree.-197.degree. C. with decomposition were obtained from 1.63 g
(2.93 mmol) of the tert.-butyl ester (Process Example 30).
NMR (270 MHz, DMSO-d.sub.6): .delta.=0.78 (m, 4H, CH.sub.2), 1.29 (t, 2H,
CH.sub.2), 1.41 (s, 1H, OH), 1.78 (dd, 1H, CH.sub.2 CO.sub.2), 1.88 (qui,
1H, CH), 2.00 (dd, 1H, CH.sub.2 CO.sub.2), 3.22 (AB part of ABX system,
2H, OCH.sub.2), 3.67 (m, 2H, CH), 4.89 (s, br., 1H, OH), 7.05 (d, 1H,
arom. H), 7.16-7.29 (m, 5H, arom. H), 7.36-7.58 (m, 4H, arom. H).
EXAMPLE 3
Sodium
3(R),5(S)-dihydroxy-6-[2-p-fluoro-a-methylphenyl-4-p-fluorophenylthio-6-is
opropyl)phenoxy]hexanoate (formula II/2)
In analogy to Example 1, 3.21 g of colorless solid (title compound) which
melts at 197.degree.-201.degree. C. with decomposition were obtained from
3.69 g (6.45 mmol) of the tert.-butyl ester (Process Example 32).
NMR (270 MHz, DMSO-d.sub.6): .delta.=1.19 (d, 6H, CH(CH.sub.3).sub.2), 1.29
(t, 2H, CH.sub.2), 1.41 (s, 1H, OH), 1.78 (dd, 1H, CH.sub.2 CO.sub.2),
1.98 (dd, 1H, CH.sub.2 CO.sub.2), 2.35 (s, 3H, CH.sub.3), 3.22 (AB part of
ABX system, 2H, OCH.sub.2), 3.47 (sept., 1H, CH(CH.sub.3).sub.2), 3.66 (m,
2H, CH), 4.90 (s, br., 1H, OH), 7.05 (d, 1H, arom. H), 7.17-7.56 (m, 8H,
arom. H).
EXAMPLE 4
Sodium
3(R),5(S)-dihydroxy-6-[2-p-fluorophenyl-4-p-phenylthio-6-isopropyl)phenoxy
]hexanoate (formula II/2)
In analogy to Example 1, 3.13 g of pale yellow solid (title compound) which
melts at 190.degree.-193.degree. C. with decomposition were obtained from
3.64 g (6.74 mmol) of the tert.-butyl ester (Process Example 34).
EXAMPLE 5
Sodium
3(R),S(S)-dihydroxy-6-[(2-p-fluorophenyl-4-isopropylthio-6-isopropyl)pheno
xy]hexanoate (formula 11/2)
In analogy to Example 1, 54 mg of yellowish solid (title compound) were
obtained from 65 mg (0.13 mmol) of the tert.-butyl ester (Process Example
36).
EXAMPLE 6
Sodium
3(R),5(S)-dihydroxy-6-(2-isopropyl-4-[(3-isopropyl-4-sodio-oxy-5-p-fluorop
henyl-l-phenylthio)-2-propyl-2-thio]-6-p-fluorophenylphenoxy)hexanoate
(formula II/2)
20.5 ml (20.5 mmol, 2.02 equivalents) of 1N sodium hydroxide solution were
added to a solution of 7.8 g (10.17 mmol) of the tert.-butyl ester
(Process Example 38) in 75 ml of ethanol and the mixture was stirred at
room temperature for 2 hours. TLC (methylene chloride/methanol 10:1)
showed complete reaction of the ester (R.sub.f =0.70) to give the polar
product (R.sub.f =0.37). Solvents were removed in vacuo. The residue was
taken up in ethanol four times and the solvent was in each case stripped
off in vacuo. The residue was washed with cyclohexane, then dried to
constant weight in a high vacuum. 7.35 g (9.74 mmol, 95.7% yield) of a
yellowish solid (title compound) which begins to melt at 185.degree. C.
with decomposition and turns into a black melt at 200.degree.-210.degree.
C. were obtained.
NMR (270 MHz, DMSO-d.sub.6): .delta.=1.14 (d, finely split, 6H,
CH(CH.sub.3).sub.2), 1.22 (d, 6H, CH(CH.sub.3).sub.2), 1.32 (t, 2H,
CH.sub.2), 1.40 (s, 6H, S--C(CH.sub.3).sub.2 --S), 1.82 (dd, 1H,, CH.sub.2
CO.sub.2), 2.03 (dd, 1H, CH.sub.2 CO.sub.2), 3.15-3.55 (m 6H, OCH.sub.2,
2 xOH, 2 xCH(CH.sub.3).sub.2), 3.68 (.about.qui, 2H, CH), 6.86 (d, 1H,
arom. H), 7.00 (AA'BB', 2H, arom. H), 7.07 (d, 1H, arom. H), 7.22 (AA'BB',
2H, arom. H), 7.33 (d, 1H, arom. H), 7.50-7.62 (m, 3H, arom. H).
EXAMPLE 7
4,4-(Isopropylidenedithio)-bis-<{1-[(2S,4R)-dihydroxy-5-sodiocarboxy]pentox
y-2-isopropyl-6-p-fluorophenyl}benzene> (formula II/2)
11.4 ml (11.4 mmol, 2.02 equivalents) of IN sodium hydroxide solution were
added to a solution of 5.5 g (5.65 mmol) of the tert.-butyl ester (Process
Example 39) in 73 ml of ethanol and the mixture was stirred at room
temperature for 2 hours. The solvent was removed in vacuo, and the residue
was taken up in methanol five times and the solution was in each case
concentrated to dryness in vacuo. The residue was washed with cyclohexane,
then dried to constant weight in a high vacuum. 5.08 g (5.64 mmol, 100%
yield) of a colorless solid which decomposes at 225.degree.-250.degree. C.
with darkening were obtained.
NMR (270 MHz, DMSO-d.sub.6): .delta.=1.21 (d, 12H, CH(H.sub.3).sub.2), 1.32
(t, 2H, CH.sub.2), 1.50 (s, 6H, S--C(CH.sub.3).sub.2 --S), 1.78 (dd, 1H,
CH.sub.2 CO.sub.2), 2.01 (dd, 1H, CH.sub.2 CO.sub.2), 3.23 (m, 4H,
OCH.sub.2), 3.39-3.56 (M, 2H, CH(CH.sub.3).sub.2), 3.58-3.74 (m, 4H, CH) ,
4.90 (s, br., 2H, OH), 7.12-7.37 and 7.48-7.62 (m, 12H, arom. H).
EXAMPLE 8
Sodium 3(R),5(S)-dihydroxy-6-[2,3,5-triisopropyl-4-
hydroxy-6-p-fluorophenyl)phenoxy]hexanoate (formula II/2)
A suspension of 363 mg (0.63 mmol) of the tert.-butyl ester (Process
Example 41) in 3.6 ml of absolute ethanol was cooled in an ice bath and
1.21 ml (1.21 mmol, 2.02 equivalents) of 1N sodium hydroxide solution were
added using a syringe. The reaction mixture was stirred at room
temperature and rapidly turned into a clear solution. TLC
(chloroform/methanol 5:1) after 3 hours showed virtually complete
conversion of the starting material (R.sub.f =0.97) to product (R.sub.f
=0.28). The solvents were stripped off, and the residue was taken up
toluene twice and in each case concentrated to dryness in vacuo. The
residue was washed twice with diisopropyl ether and once with ether, and
gave 345 mg of a colorless, fine powder which decomposed and melted at
239.degree.-242.degree. C. while turning brown. This material contained 1
mol equivalent of sodium acetate. Its empirical formula was thus
C.sub.27 H.sub.36 FO.sub.6 Na.times.C.sub.2 H.sub.3 O.sub.2 Na=C.sub.29
H.sub.39 FO.sub.8 Na.sub.2 (MW 580.60).
The yield of title compound was 94%.
EXAMPLE 9
Sodium
3(R),5(S)-dihydroxy-6-[2,5,6-triisopropyl-3-p-fluorophenyl)-4-hydroxy)phen
oxy]hexanoate (formula II/2)
A suspension of 549 mg (0.96 mmol) of the tert.-butyl ester (Process
Example 43,) in 5.8 ml of absolute ethanol was cooled in an ice bath and
1.94 ml (1.94 mmol, 2.02 equiv.) of 1N sodium hydroxide solution were
added using a syringe. In contrast to Example 8, the reaction mixture
remained a suspension. In spite of this, TLC showed a virtually
quantitative conversion after 3 hours. Working up as in Example 8 gave 519
mg of a colorless solid which decomposed and melted at
239.degree.-240.degree. C. while turning brown. This material contained 1
mol equivalent of sodium acetate. Its empirical formula was thus C.sub.29
H.sub.39 FO.sub.8 Na.sub.2 (MW 580.60). The yield of title compound was
93.6%.
EXAMPLE 10
4(R)-Hydroxy-6(S)-[(2-p-fluorophenyl-4-p-fluorophenylthio-6-isopropyl)pheno
xymethyl]-3,4,5,6-tetrahydro-2H-pyran-2-one (formula I)
5 ml of trifluoroacetic acid were added dropwise to a solution of 5.59 g
(10.2 mmol) of the tert.-butyl ester (Process Example 28) in 20 ml of
methylene chloride. The reaction mixture was stirred at room temperature
for 2 hours. TLC (cyclohexane/ethyl acetate 1:1) showed quantitative
conversion of the tert.-butyl ester (R.sub.f =0.37) to the lactone
(R.sub.f =0.12) and insignificant non-polar impurities. The reaction
mixture was neutralized using sodium hydrogen carbonate powder, then
rendered neutral using sodium carbonate powder, and then poured into water
and extracted several times using ether. The combined organic phases were
washed with sodium hydrogen carbonate solution and then with sodium
chloride solution, dried, filtered and concentrated. The residue was
chromatographed through a silica gel column using cyclohexane/ethyl
acetate 1:1 and gave 3.88 g (8.0 mmol, yield 80%) of a colorless solid
(title compound), melting point 108.degree.-110.degree. C.
NMR (270 MHz): .delta.=1.30+1.32 (2 xd, 6H, CH(CH.sub.3).sub.2), 1.72-1.94
(m, 3H, CH.sub.2 and OH), 2.67 (AB part of ABX system, 2H, CH.sub.2
CO.sub.2), 3.47 (sept., 1H, CH(CH.sub.3).sub.2), 3.59 (AB part of ABX
system, 2H, OCH.sub.2), 4.40 (m, 1H, CH--OH), 4.72 (m, 1H, CH--OCO),
6.80-7.55 (m, 10H, arom. H).
MS (DCI, isobutane): m/e=484 (M.sup.+), 467 (M.sup.+ -OH),
##STR33##
EXAMPLE 11
Sodium
3(R),5(S)-dihydroxy-6-[(2-p-fluorophenyl-4-p-fluorophenylthio-6-isopropyl)
phenoxy]hexanoate (formula II/2)
1.0 ml (1.0 mmol) of 1N sodium hydroxide solution was added with
ice-cooling to a solution of 485 mg (1. 0 mmol) of the lactone (Example
10) in 10 ml of ethanol and the mixture was stirred at 0.degree. C. for 2
hours. The solvents were removed in vacuo. The residue was taken up in
toluene twice and the solution was in each case concentrated to dryness in
vacuo. The residue was washed with n-pentane and dried to constant weight
in a high vacuum. 512 mg (0.98 mmol, 97.6% yield) of a solid (title
compound) which is identical with that from Example 1 were obtained.
EXAMPLE 12
4(R)-Hydroxy-6(S)-[(2-p-fluorophenyl-4-p-fluorophenylthio-6-isopropyl)pheno
xymethyl]-3,4,5,6-tetrahydro-2H-pyran-2-one (formula I)
1.05 g (2.0 mmol) of the sodium carboxylate (Example 1) were largely
dissolved in 32 ml of distilled water. 2 ml of 2N hydrochloric acid (4.0
mmol, 2 equivalents) were added with ice-cooling. The carboxylic acid
which precipitated in crystalline form was extracted using ethyl acetate
(2.times.20 ml). The extracts were washed twice with saturated sodium
chloride solution, briefly dried, filtered and concentrated in vacuo, and
the residue was dried in a high vacuum. Yield 1.00 g (1.99 mmol) of
colorless solid. This free carboxylic acid was dissolved in 10 ml of
absolute THF and 302 .mu.l (221.5 mg, 2.19 mmol, 1.1 equivalents) of
triethylamine were rapidly added dropwise at 0.degree.-10.degree. C., the
mixture was stirred at 0.degree. C. for 10 min and then cooled to
-10.degree. C., and 200 .mu.l (226.8 mg, 2.09 mmol, 1.05 equivalents) of
ethyl chloroformate were slowly added dropwise. The reaction mixture was
stirred at -5.degree. C. for 1 hour and partitioned between ether and
semi-saturated sodium chloride solution, and the phases were separated.
The aqueous phase was extracted two more times using ether and the
combined extracts were again washed with sodium chloride solution.
The extracts were dried, filtered and concentrated in vacuo, and the
residue was chromatographed through a silica gel column using
cyclohexane/ethyl acetate 1:1.
820 mg (1.69 mmol, 85% yield) of a colorless solid (title compound) which
was identical with that from Example 10 were obtained.
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